New Positive Allosteric Modulators or Nicotinic Acetylcholine Receptor

ABSTRACT

The present invention relates to compounds useful in therapy, to compositions comprising said compounds, and to methods of treating diseases comprising administration of said compounds. The compounds referred to are positive allosteric modulators (PAMs) of the nicotinic acetylcholine α7 receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.14/704,038 (which was filed on May 5, 2015; pending), which applicationis a divisional application of U.S. patent application Ser. No.14/054,941 (which was filed on Oct. 16, 2013, and which issued on Jun.9, 2015 as U.S. Pat. No. 9,050,327), which application was acontinuation of U.S. patent application Ser. No. 13/542,687 (which wasfiled on Jul. 6, 2012, and which issued on Dec. 3, 2013 as U.S. Pat. No.8,598,213), which application claims the benefit of priority under 35U.S.C. §119(e) of U.S. Provisional Application No. 61/505,847, filedJul. 8, 2011. Each of these applications is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds useful in therapy, tocompositions comprising said compounds, and to methods of treatingdiseases comprising administration of said compounds. The compoundsreferred to are positive allosteric modulators (PAMs) of the nicotinicacetylcholine α7 receptor.

BACKGROUND OF THE INVENTION

Nicotinic acetylcholine receptors (nAChRs) belong to the super family ofligand gated ionic channels, and gate the flow of cations includingcalcium. The nAChRs are endogenously activated by acetylcholine (ACh)and can be divided into nicotinic receptors of the neuromuscularjunction and neuronal nicotinic receptors (NNRs). The NNRs are widelyexpressed throughout the central nervous system (CNS) and the peripheralnervous system (PNS). The NNRs have been suggested to play an importantrole in CNS function by modulating the release of manyneurotransmitters, for example, ACh, norepinephrine, dopamine,serotonin, and GABA, among others, resulting in a wide range ofphysiological effects.

Seventeen subunits of nAChRs have been reported to date, which areidentified as α2-α10, β1-β4, γ, δ and ε. From these subunits, ninesubunits, α2 through α7 and β2 through β4, prominently exist in themammalian brain. Many functionally distinct nAChR. complexes exist, forexample five α7 subunits can form a receptor as a homomeric functionalpentamer or combinations of different subunits can form heteromericreceptors such as α4β2 and α3β4 receptors (Gotti, C. et al., Prog.Neurobiol., 2004, 74: 363-396; Gotti, C. et al., BiochemicalPharmacology, 2009, 78: 703-711).

The homomeric α7 receptor is one of the most abundant NNRs, along withα4β2 receptors, in the brain, wherein it is heavily expressed in thehippocampus, cortex, thalamic nuclei, ventral tegmental area andsubstantia nigra (Broad, L. M. et al., Drugs of the Future, 2007, 32(2):161-170, Poorthuis R B, Biochem Pharmacol. 2009, 1; 78(7):668-76).

The role of α7 NNR in neuronal signalling has been activelyinvestigated. The α7 NNRs have been demonstrated to regulate interneuronexcitability and modulate the release of excitatory as well asinhibitory neurotransmitters. In addition, α7 NNRs have been reported tobe involved in neuroprotective effects in experimental models ofcellular damage (Shimohama, S., Biol Pharm Bull. 2009, 32(3):332-6).Studies have shown that α7 subunits, when expressed recombinantin-vitro, activate and desensitize rapidly, and exhibit relativelyhigher calcium permeability compared to other NNR combinations (Papke,R. L. et al., J Pharmacol Exp Ther. 2009, 329(2):791-807).

The NNRs, in general, are involved in various cognitive functions, suchas learning, memory and attention, and therefore in CNS disorders, i.e.,Alzheimer's disease (AD), Parkinson's disease (PD), attention deficithyperactivity disorder (ADHD), Tourette's syndrome, schizophrenia,bipolar disorder, pain and tobacco dependence (Keller, J. J. et al.,Behav. Brain Res. 2005, 162: 143-52; Haydar, S. N. et al., Curr Top MedChem. 2010; 10(2):144-52).

The α7 NNRs in particular, have also been linked to cognitive disordersincluding, for example, ADHD, autism spectrum disorders, AD, mildcognitive impairment (MCI), age associated memory impairment (AAMI)senile dementia, frontotemporal lobar degeneration, HIV associateddementia (HAD), HIV associated cognitive impairment (HIV-CI), Pick'sdisease, dementia associated with Lewy bodies, cognitive impairmentassociated with Multiple Sclerosis, Vascular Dementia, cognitiveimpairment in Epilepsy, cognitive impairment associated with fragile X,cognitive impairment associated with Friedreich's Ataxia, and dementiaassociated with Down's syndrome, as well as cognitive impairmentassociated with schizophrenia. In addition, α7-NNRs have been shown tobe involved in the neuroprotective effects of nicotine both in vitro(Jonnala, R. B. et al., J. Neurosci. Res., 2001, 66: 565-572) and invivo (Shimohama, S., Brain Res., 1998, 779: 359-363) as well as in painsignalling. More particularly, neurodegeneration underlies severalprogressive CNS disorders, including, but not limited to, AD, PD,amyotrophic lateral sclerosis, Huntington's disease, dementia with Lewybodies, as well as diminished CNS function resulting from traumaticbrain injury. For example, the impaired function of α7 NNRs bybeta-amyloid peptides linked to AD has been implicated as a key factorin development of the cognitive deficits associated with the disease(Liu, Q.-S., et al., PNAS, 2001, 98: 4734-4739). Thus, modulating theactivity of α7 NNRs demonstrates promising potential to prevent or treata variety of diseases indicated above, such as AD, other dementias,other neurodegenerative diseases, schizophrenia and neurodegeneration,with an underlying pathology that involves cognitive function including,for example, aspects of learning, memory, and attention (Thomsen, M. S.et al., Curr Pharm Des. 2010 January; 16(3):323-43; Olincy. A. et al.,Arch Gen Psychiatry. 2006, 63(6):630-8: Deutsch, S. I., ClinNeuropharmacol. 2010, 33(3):114-20; Feuerbach, D., Neuropharmacology2009, 56(1): 254-63)

The NNR ligands, including α7 ligands, have also been implicated inweight control, diabetis inflammation, obsessive-compulsive disorder(OCD), angiogenesis and as potential analgesics (Marrero, M. B. et al.,J. Pharmacol. Exp. Ther. 2010, 332(1):173-80; Vincler, M., Exp. Opin.Invest. Drugs, 2005, 14 (10): 1191-1198; Rosas-Ballina, M., J. InternMed. 2009 265(6):663-79; Arias, H. R., Int, J. Biochem. Cell Biol. 2009,41(7):1441-51; Tizabi, Y., Biol Psychiatry. 2002, 51(2):164-71).

Nicotine is known to enhance attention and cognitive performance,reduced anxiety, enhanced sensory gating, and analgesia andneuroprotective effects when administered. Such effects are mediated bythe non-selective effect of nicotine at multiple nicotinic receptorsubtypes. However, nicotine also exerts adverse events, such ascardiovascular and gastro-intestinal problems (Karaconji, I. B. et al.,Arh Hig Rada Toksikol 2005, 56(4):363-71). Consequently, there is a needto identify subtype-selective compounds that retain the beneficialeffects of nicotine, or an NNR ligand, while eliminating or decreasingadverse effects.

Examples of reported NNR ligands are α7 NNR agonists, such as DMXB-A,SSR180711 and ABT-107, which have shown some beneficial effects oncognitive processing both in rodents and humans (H312: 1213-22; Olincy,A. et al., Arch Gen Psychiatry. 2006 63(6):630-8; Pichat, P., et al.,Neuropsychopharmacology. 2007 32(1):17-34; Bitner, R. S., J PharmacolExp Ther. 2010 1; 334(3):875-86). In addition, modulation of α7 NNRshave been reported to improve negative symptoms in patients withschizophrenia (Freedman, R. et al., Am J Psychiatry. 2008165(8):1040-7).

Despite the beneficial effects of NNR ligands, it remains uncertainwhether chronic treatment with agonists affecting NNRs may providesuboptimal benefit due to sustained activation and desensitization ofthe NNRs, in particular the α7 NNR subtype. In contrast to agonists,administering a positive allosteric modulator (PAM) can reinforceendogenous cholinergic transmission without directly stimulating thetarget receptor. Nicotinic PAMs can selectively modulate the activity ofACh at NNRs, preserving the activation and deactivation kinetics of thereceptor. Accordingly, α7 NNR-selective PAMs have emerged (Faghih, R.,Recent Pat CNS Drug Discov. 2007, 2(2):99-106).

Consequently, it would be beneficial to increase α7 NNR function byenhancing the effect of the endogenous neurotransmitter acetylcholinevia PAMs. This could reinforce the endogenous cholinergicneurotransmission without directly activating α7 NNRs, like agonists.Indeed, PAMs for enhancing channel activity have been proven clinicallysuccessful for GABAa receptors where benzodiazepines and barbiturates,behave as PAMs acting at distinct sites (Hevers, W. et al., Mol.Neurobiol., 1998, 18: 35-86).

To date, only a few NNR PAMs are known, such as 5-hydroxyindole (5-HI),ivermectin, galantamine, and SLURP-1, a peptide derived fromacetylcholinesterase (AChE). Genistein, a kinase inhibitor was alsoreported to increase α7 responses. PNU-120596, a urea derivative, wasreported to increase the potency of ACh as well as improve auditorygating deficits induced by amphetamine in rats. Also, NS1738,JNJ-1930942 and compound 6 have been reported to potentiate the responseof ACh and exert beneficial effect in experimental models of sensory andcognitive processing in rodents. Other NNR PAMs include derivatives ofquinuclidine, indole, benzopyrazole, thiazole, and benzoisothiazoles(Hurst, R. S. et al., J. Neurosci. 2005, 25: 4396-4405; Faghih, R.,Recent Pat CNS Drug Discov. 2007, 2(2):99-106; Timmermann, O. B., J.Pharmacol Exp. Ther. 2007, 323(1):294-307; Ng, H. J. et al, Proc. Natl.Acad. Sci. USA. 2007, 8; 104(19):8059-64; Dinklo, T., J. Pharmacol. Exp.Ther. 2011, 336(2):560-74.).

WO 2009/043764 recites compounds of the overall structure

which compounds are said to be PAMs of the α7 NNR.

The α7 NNR PAMs presently known generally demonstrate weak activity,have a range of non-specific effects, or can only achieve limited accessto the central nervous system where α7 NNRs are abundantly expressed.Accordingly, it would be beneficial to identify and provide new PAMcompounds of α7 NNRs and compositions for treating diseases anddisorders wherein α7 NNRs are involved. It would further be particularlybeneficial if such compounds can provide improved efficacy of treatmentwhile reducing adverse effects associated with compounds targetingneuronal nicotinic receptors by selectively modulating α7 NNRs.

WO 2010/137351 recites compounds of the overall structure

as calcium or sodium channel blockers. Compound examples disclosed in WO2010/137351 are not intended to be included in the present invention.

Particularly the compounds (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide,(1S,2S)-2-(2-Chloro-4-fluoro-phenyl)-cyclopropanecarboxylic acid{(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide and(1S,2S)-2-(2-Fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid{(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide aredisclosed in WO 2010/137351 are disclaimed from the present invention

SUMMARY OF THE INVENTION

The objective of the present invention is to provide compounds that arepositive allosteric modulators (PAMs) of the nicotinic acetylcholinereceptor subtype α7.

The compounds of the present invention are defined by formula [I] below:

wherein R1, R2, R3, R4 and R5 are selected independently of each otherfrom H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, cyano andhalogen, wherein said C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl isoptionally substituted with one or more substituents independentlyselected from chlorine and fluorine;R6 is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and C₁₋₆alkoxy,wherein said C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl is optionallysubstituted with one or more substituents independently selected fromhydroxy, C₁₋₆alkoxy and fluorine;A7 is C—R7 or N, A8 is C—RB or N and A9 is C—R9 or N, provided that atleast one of A7, A8 or and 9 is N and no more than two of A7, A8 and A9is N;R7, R8, R9, R10 and R11 are selected independently of each other from H,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, cyano, NR12R13,C₁₋₆alkylsulfonyl, halogen and OR14, wherein said C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkoxy is optionally substituted withone or more substituents selected from chlorine, fluorine, C₁₋₆alkoxy,cyano and NR12R13;R12 and R13 independently represent hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl andC₂₋₆alkynyl;R14 represents a monocyclic saturated ring moiety having 4-6 ring atomswherein one of said ring atoms is O and the others are C;or R9 and R10 may be linked together to form the moiety indicated below

wherein n is 1, 2 or 3;and pharmaceutically acceptable salts thereof;with the proviso that the compound of formula [I] is other than

-   (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    {(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide;-   (1S,2S)-2-(2-Chloro-4-fluoro-phenyl)-cyclopropanecarboxylic acid    {(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide;-   (1S,2S)-2-(2-Fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid    {(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide.

In one embodiment, the invention relates to a compound according toformula [I], and pharmaceutically acceptable salts thereof, for use as amedicament.

In one embodiment, the invention relates to a compound according toformula [I], and pharmaceutically acceptable salts thereof, for use intherapy.

In one embodiment, the invention relates to a compound according toformula [I], and pharmaceutically acceptable salts thereof, for use inthe treatment of a disease or disorder selected from Psychosis;Schizophrenia; cognitive disorders; cognitive impairment associated withschizophrenia; Attention Deficit Hyperactivity Disorder (ADHD); autismspectrum disorders, Alzheimer's disease (AD); mild cognitive impairment(MCI); age associated memory impairment (AAMI); senile dementia; AIDSdementia; Pick's disease; dementia associated with Lewy bodies; dementiaassociated with Down's syndrome; Huntington's Disease; Parkinson'sdisease (PD); obsessive-compulsive disorder (OCD); traumatic braininjury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome(WKS); post-traumatic amnesia: cognitive deficits associated withdepression; diabetes, weight control, inflammatory disorders, reducedangiogenesis; amyotrophic lateral sclerosis and pain.

In one embodiment, the invention relates to a pharmaceutical compositioncomprising a compound according to formula [I] and pharmaceuticallyacceptable salts thereof, and one or more pharmaceutically acceptablecarrier or excipient.

In one embodiment, the invention relates to a kit comprising a compoundaccording to formula [I], and pharmaceutically acceptable salts thereof,together with a compound selected from the list consisting ofacetylcholinesterase inhibitors; glutamate receptor antagonists;dopamine transport inhibitors; noradrenalin transport inhibitors; D2antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A antagonists;5-HT6 antagonists; KCNQ antagonists; lithium; sodium channel blockersand GABA signaling enhancers.

In one embodiment, the invention relates to a method for the treatmentof a disease or disorder selected from Psychosis; Schizophrenia;cognitive disorders; cognitive impairment associated with schizophrenia;Attention Deficit Hyperactivity Disorder (ADHD); autism spectrumdisorders, Alzheimer's disease (AD); mild cognitive impairment (MCI);age associated memory impairment (AAMI); senile dementia; AIDS dementia;Pick's disease; dementia associated with Lewy bodies; dementiaassociated with Down's syndrome; Huntington's Disease; Parkinson'sdisease (PD); obsessive-compulsive disorder (OCD); traumatic braininjury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome(WKS); post-traumatic amnesia; cognitive deficits associated withdepression; diabetes, weight control, inflammatory disorders, reducedangiogenesis; amyotrophic lateral sclerosis and pain, which methodcomprises the administration of a therapeutically effective amount of acompound according to formula [I], and pharmaceutically acceptable saltsthereof.

In one embodiment, the invention relates to the use of a compoundaccording to formula [I], and pharmaceutically acceptable salts thereof,for the manufacture of a medicament for the treatment of a disease ordisorder selected from Psychosis; Schizophrenia; cognitive disorders;cognitive impairment associated with schizophrenia; Attention DeficitHyperactivity Disorder (ADHD); autism spectrum disorders, Alzheimer'sdisease (AD); mild cognitive impairment (MCI); age associated memoryimpairment (AAMI); senile dementia; AIDS dementia; Pick's disease;dementia associated with Lewy bodies; dementia associated with Down'ssyndrome; Huntington's Disease; Parkinson's disease (PD);obsessive-compulsive disorder (OCD); traumatic brain injury; epilepsy;post-traumatic stress; Wernicke-Korsakoff syndrome (WKS); post-traumaticamnesia; cognitive deficits associated with depression; diabetes, weightcontrol, inflammatory disorders, reduced angiogenesis; amyotrophiclateral sclerosis and pain.

DEFINITIONS

In the present context, “optionally substituted” means that theindicated moiety may or may not be substituted, and when substituted ismono-, di-, or tri-substituted, such as with 1, 2 or 3 substituents. Insome instances, the substituent is independently selected from the groupconsisting of C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, phenyl, C₁₋₆alkoxy,hydroxy and halogen. It is understood that where no substituents areindicated for an “optionally substituted” moiety, then the position isheld by a hydrogen atom.

In the present context, “alkyl” is intended to indicate a straight,branched and/or cyclic saturated hydrocarbon. In particular “C₁₋₆alkyl”is intended to indicate such hydrocarbon having 1, 2, 3, 4, 5 or 6carbon atoms. Examples of C₁₋₆alkyl include methyl, ethyl, propyl,butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methylcyclopropyl, 2-methylpropyl and tert-butyl. Examples ofsubstituted C₁₋₆alkyl include e.g. fluoromethyl and hydroxymethyl.

In the present context, “alkenyl” is intended to indicate anon-aromatic, straight, branched and/or cyclic hydrocarbon comprising atleast one carbon-carbon double bond. In particular “C₂₋₆alkenyl” isintended to indicate such hydrocarbon having 2, 3, 4, 5 or 6 carbonatoms. Examples of C₂₋₆alkenyl include ethenyl, 1-propenyl, 2-propenyl,1-butenyl, 2-butenyl and 3-butenyl and cyclohexenyl.

In the present context, “alkynyl” is intended to indicate anon-aromatic, straight, branched and/or cyclic hydrocarbon comprising atleast one carbon-carbon triple bond and optionally also one or morecarbon-carbon double bonds. In particular “C₂₋₆alkynyl” is intended toindicate such hydrocarbon having 2, 3, 4, 5 or 6 carbon atoms. Examplesof C₂₋₆alkynyl include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,2-butynyl, 3-butynyl and 5-but-1-en-3-ynyl.

In the present context, “hydroxy” is intended to indicate —OH.

In the present context, “alkoxy” is intended to indicate a moiety of theformula —OR′, wherein R′ indicates alkyl as defined above. In particular“C₁₋₆alkoxy” is intended to indicate such moiety wherein the alkyl parthas 1, 2, 3, 4, 5 or 6 carbon atoms. Examples of “C₁₋₆alkoxy” includemethoxy, ethoxy, n-butoxy and tert-butoxy.

In the present context, “alkylsulfonyl” is intended to indicate—S(O)₂alkyl In particular C₁₋₆alkylsulfonyl is intended to indicate sucha moiety wherein the alkyl part has 1, 2, 3, 4, 5 or 6 carbon atoms.Particular mention is made of methylsulfonyl.

In the present context, a “monocyclic moiety” is intended to cyclicmoiety comprising only one ring, said cyclic moiety can be saturated orunsaturated.

In the present context, the terms “halo” and “halogen” are usedinterchangeably and refer to fluorine, chlorine, bromine or iodine.

In the present context, the term “cyano” indicates the group —C≡N, whichconsists of a carbon atom triple-bonded to a nitrogen atom.

In the present context, “ring atom” is intended to indicate the atomsconstituting a ring, and ring atoms are selected from C, N, O and S. Asan example, benzene and toluene both have 6 carbons as ring atomswhereas pyridine has 5 carbons and 1 nitrogen as ring atoms.

In the present context, “heteroatom” means a nitrogen, oxygen or sulfuratom.

In the present context, “deuterium” indicates the atomic isotope ofhydrogen consisting of one proton and one neutron in its nucleus, andthus having an approximate weight of two (2). Deuterium is representedas D, d or ²H. An example of a substituent comprising deuterium is(2,2,2-d₃)-ethoxy wherein three of the hydrogens in ethoxy are the ²Hisotopes.

In the present context, “enantiomeric excess” represents the % excess ofa compound in a mixture of compound enantiomers. If for example anenantiomeric excess is 90% then the ratio of the compound to itsenantiomer is 95:5 and if an enantiomeric excess is 95% then the ratioof the compound to its enantiomer is 97.5:2.5. Likewise, “diastereomericexcess” represents % excess of a compound in a mixture of compounddiastereomers.

In the present context, pharmaceutically acceptable salts includepharmaceutically acceptable acid addition salts, pharmaceuticallyacceptable metal salts, ammonium and alkylated ammonium salts. Acidaddition salts include salts of inorganic acids as well as organicacids.

Examples of suitable inorganic acids include hydrochloric, hydrobromic,hydroiodic, phosphoric, sulfuric, sulfamic, nitric acids and the like.

Examples of suitable organic acids include formic, acetic,trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric,fumaric, glycolic, itaconic, lactic, methanesulfonic, maleic, malic,malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylenesalicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic,palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic,p-toluenesulfonic acids, theophylline acetic acids, as well as the8-halotheophyllines, for example 8-bromotheophylline and the like.Further examples of pharmaceutical acceptable inorganic or organic acidaddition salts include the pharmaceutically acceptable salts listed inBerge, S. M. et al., J. Pharm. Sci 1977, 66, 2, which is incorporatedherein by reference.

Examples of metal salts include lithium, sodium, potassium, magnesiumsalts and the like.

Examples of ammonium and alkylated ammonium salts include ammonium,methyl-, dimethyl-, trimethyl-, ethyl-, hydroxyethyl-, diethyl-,n-butyl-, sec-butyl-, tert-butyl-, tetramethylammonium salts and thelike.

In the present context, pharmaceutical carriers include inert soliddiluents or fillers, sterile aqueous solutions and various organicsolvents. Examples of solid carriers include lactose, terra alba,sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesiumstearate, stearic acid and lower alkyl ethers of cellulose. Examples ofliquid carriers include, but are not limited to, syrup, peanut oil,olive oil, phospholipids, fatty acids, fatty acid amines,polyoxyethylene and water. Similarly, the carrier may include anysustained release material known in the art, such as glycerylmonostearate or glyceryl distearate, alone or mixed with a wax.

In the present context, the term “therapeutically effective amount” of acompound means an amount sufficient to cure, alleviate or partiallyarrest the clinical manifestations of a given disease and itscomplications in a therapeutic intervention comprising theadministration of said compound. An amount adequate to accomplish thisis defined as “therapeutically effective amount”. Effective amounts foreach purpose will depend on the severity of the disease or injury aswell as the weight and general state of the subject. It will beunderstood that determining an appropriate dosage may be achieved usingroutine experimentation, by constructing a matrix of values and testingdifferent points in the matrix, which is all within the ordinary skillsof a trained physician.

In the present context, the term “treatment” and “treating” means themanagement and care of a patient for the purpose of combating acondition, such as a disease or a disorder. The term is intended toinclude the full spectrum of treatments for a given condition from whichthe patient is suffering, such as administration of the active compoundto alleviate the symptoms or complications, to delay the progression ofthe disease, disorder or condition, to alleviate or relief the symptomsand complications, and/or to cure or eliminate the disease, disorder orcondition as well as to prevent the condition, wherein prevention is tobe understood as the management and care of a patient for the purpose ofcombating the disease, condition, or disorder and includes theadministration of the active compounds to prevent the onset of thesymptoms or complications. Nonetheless, prophylactic (preventive) andtherapeutic (curative) treatments are two separate aspects of thepresent invention. The patient to be treated is preferably a mammal, inparticular a human being.

In the present context, the term “cognitive disorders” is intended toindicate disorders characterized by abnormalities in aspects ofperception, problem solving, language, learning, working memory, memory,social recognition, attention and pre-attentional processing, such as bynot limited to Attention Deficit Hyperactivity Disorder (ADHD), autismspectrum disorders, Alzheimer's disease (AD), mild cognitive impairment(MCI), age associated memory impairment (AAMI), senile dementia,vascular dementia, frontotemporal lobe dementia, Pick's disease,dementia associated with Lewy bodies, and dementia associated withDown's syndrome, cognitive impairment associated with MultipleSclerosis, cognitive impairment in epilepsy, cognitive impairmentassociated with fragile X, cognitive impairment associated withneurofibromatosis, cognitive impairment associated with Friedreich'sAtaxia, progressive supranuclear palsy (PSP), HIV associated dementia(HAD), HIV associated cognitive impairment (HIV-CI), Huntington'sDisease, Parkinson's disease (PO), obsessive-compulsive disorder (OCD),traumatic brain injury, epilepsy, post-traumatic stress,Wernicke-Korsakoff syndrome (WKS), post-traumatic amnesia, cognitivedeficits associated with depression as well as cognitive impairmentassociated with schizophrenia.

The cognitive enhancing properties of a compound can be assessed e.g. bythe attentional set-shifting paradigm which is an animal model allowingassessment of executive functioning via intra-dimensional (ID) versusextra-dimensional (ED) shift discrimination learning. The study can beperformed by testing whether the compound is attenuating “attentionalperformance impairment” induced by subchronic PCP administration in ratsas described by Rodefer, J. S. et al., Eur. J. Neurosci. 2005,21:1070-1076.

In the present context, the term “autism spectrum disorders” is intendedto indicate disorders characterized by widespread abnormalities ofsocial interactions and verbal and non-verbal communication, as well asrestricted interests, repetitive behavior and attention, such as by notlimited to autism, Asperger syndrome, Pervasive Developmental DisorderNot Otherwise Specified (PDD-NOS), Rett syndrome, Angelmann syndrome,fragile X, DiGeorge syndrome and Childhood Disintegrative Disorder.

In the present context, the term “inflammatory disorders” is intended toindicate disorders characterized by abnormalities in the immune systemsuch as by not limited to, allergic reactions and myopathies resultingin abnormal inflammation as well as non-immune diseases with etiologicalorigins in inflammatory processes are thought to include but not belimited to cancer, atherosclerosis, osteoarthritis, rheumatoid arthritisand ischaemic heart disease.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that certain new compounds are positiveallosteric modulators (PAMs) of NNRs, and as such may be used in thetreatment of various disorders.

PAMs of NNRs may be dosed in combination with other drugs in order toachieve more efficacious treatment in certain patient populations. An α7NNR PAM may act synergistically with another drug, this has beendescribed in animals for the combination of compounds affectingnicotinic receptors, including 7 NNRs and D2 antagonism (Wiker, C., Int.J. Neuropsychopharmacol. 2008, 11 (6):845-50).

Thus, compounds of the present invention may be useful treatment in thecombination with another drug e.g. selected from acetylcholinesteraseinhibitors, glutamate receptor antagonists, dopamine transportinhibitors, noradrenalin transport inhibitors, D2 antagonists, D2partial agonists, PDE10 antagonists, 5-HT2A antagonists, 5-HT6antagonists and KCNQ antagonists, lithium, sodium channel blockers, GABAsignalling enhancers.

In one embodiment, compounds of the present invention are used fortreatment of patients who are already in treatment with another drugselected from the list above. In one embodiment, compounds of thepresent invention are adapted for administration simultaneous with saidother drug. In one embodiment compounds of the present invention areadapted for administration sequentially with said other drug. In oneembodiment, compounds of the present invention are used as the solemedicament in treatment of a patient. In one embodiment, compounds ofthe present invention are used for treatment of patients who are notalready in treatment with another drug selected from the list above.

Embodiments According to the Invention

In the following, embodiments of the invention are disclosed. The firstembodiment is denoted E1, the second embodiment is denoted E2 and soforth.

E1. A compound according to formula [I]

wherein R1, R2, R3, R4 and R5 are selected independently of each otherfrom H. C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, cyano andhalogen, wherein said C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl isoptionally substituted with one or more substituents independentlyselected from chlorine and fluorine;R6 is selected from C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl and C₁₋₆alkoxy,wherein said C₁₋₆alkyl, C₂₋₆alkenyl and C₂₋₆alkynyl is optionallysubstituted with one or more substituents independently selected fromhydroxy, C₁₋₆alkoxy and fluorine;A7 is C—R7 or N, A8 is C—R8 or N and A9 is C—R9 or N, provided that atleast one of A7, A8 or and 9 is N and no more than two of A7, A8 and A9is N;R7, R8, R9. R10 and R11 are selected independently of each other from H,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, cyano, NR12R13,C₁₋₆alkylsufonyl, halogen and OR14, wherein said C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl or C₁₋₆alkoxy is optionally substituted with one or moresubstituents selected from chlorine, fluorine, C₁₋₆alkoxy, cyano andNR12R13;R12 and R13 independently represent hydrogen, C₁₋₆alkyl, C₂₋₆alkenyl andC₂₋₆alkynyl;R14 represents a monocyclic saturated ring moiety having 4-6 ring atomswherein one of said ring atoms is O and the others are C;or R9 and R10 may be linked together to form the moiety indicated below

wherein n is 1, 2 or 3;and pharmaceutically acceptable salts thereof;with the proviso that the compound of formula [I] is other than

-   (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    {(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide;-   (1S,2S)-2-(2-Chloro-4-fluoro-phenyl)-cyclopropanecarboxylic acid    {(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide;-   (1S,2S)-2-(2-Fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid    {(S)-1-[5-(2,2,2-trifluoro-ethoxy)-pyridin-2-yl]-ethyl}-amide.    E2. The compound according to embodiment 1, wherein R1, R2, R3, R4    and R5 are selected independently of each other from H, methyl,    fluorine and chlorine;    R6 is selected from methyl, hydroxymethyl, methoxymethyl and    fluoromethyl;    R7, R8, R9, R10 and R11 are selected independently of each other    from H, C₁₋₄alkyl, C₁₋₄alkoxy; cyano, —N(CH₃)₂, methylsulfonyl,    fluorine, chlorine and OR14, wherein said C₁₋₄alkyl or C₁₋₄alkoxy is    optionally substituted with one or more substituents selected from    fluorine, C₁₋₄alkoxy and cyano;    R14 represents a monocyclic saturated ring moiety having 4-6 ring    atoms wherein one of said ring atoms is O and the others are C;    or R9 and R10 may be linked together to form the moiety indicated    below

wherein n is 1 or 2.E3, The compound according to any of embodiments 1-2, wherein R1, R2,R3, R4 and R5 are selected independently of each other from H, methyl,fluorine and chlorine.E4. The compound according to any of embodiments 1-3, wherein four ormore of R1, R2. R3, R4 and R5 are H.E5. The compound according to embodiment 4, wherein all of R1, R2, R3,R4 and R5 are H.E6. The compound according to any of embodiments 1-5, wherein R6 isselected from methyl, hydroxymethyl, methoxymethyl and fluoromethyl.E7. The compound according to embodiment 6, wherein R6 is methyl.E8. The compound according to embodiment 6, wherein R6 is hydroxymethyl.E9. The compound according to embodiment 6, wherein R6 is methoxymethyl.

E10. The compound according to embodiment 6, wherein R6 is fluoromethyl.

E11. The compound according to any of embodiments 1-10, wherein R7, R8,R9, R10 and R11 are selected independently of each other from H,C₁₋₄alkyl, C₁₋₄alkoxy, cyano, —N(CH₃)₂, methylsulfonyl, fluorine,chlorine and OR14, wherein said C₁₋₄alkyl or C₁₋₄alkoxy is optionallysubstituted with one or more substituents selected from fluorine,C₁₋₄alkoxy and cyano;R14 represents a monocyclic saturated ring moiety having 4-6 ring atomswherein one of said ring atoms is O and the others are C;or R9 and R10 may be linked together to form the moiety indicated below

wherein n is 1 or 2;E12. The compound according to any of embodiments 1 and 3-11, whereinR7, R8, R9, R10 and R11 are selected independently from H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxy, cyano or halogen, wherein saidC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl or C₁₋₆alkoxy is optionallysubstituted with one or more substituents selected from fluorine,C₁₋₆alkoxy and cyano.E13. The compound according to any of embodiments 1-12, wherein R7, R8,R9, R10 and R11 are selected independently from H, C₁₋₄alkyl.C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, cyano and halogen, wherein saidC₁₋₄alkyl, C₁₋₄alkenyl, C₂₋₄alkynyl or C₁₋₄alkoxy is optionallysubstituted with one or more substituents selected from fluorine andC₁₋₄alkoxy.E14. The compound according to any of embodiments 1-13, wherein one ormore of the hydrogen atoms are represented by deuterium.E15. The compound according to embodiment 14, wherein one or more of thehydrogen atoms in R7, R8, R9, R10 and R11 are represented by deuterium.E16. The compound according to any of embodiments 14-15, wherein atleast about 85% of the compound has a deuterium atom at each positiondesignated as deuterium, and any atom not designated as deuterium ispresent at about its natural isotopic abundance.E17. The compound according to embodiment 16, wherein at least about 90%of the compound has a deuterium atom at each position designated asdeuterium, and any atom not designated as deuterium is present at aboutits natural isotopic abundance.E18. The compound according to any of embodiments 1-17, wherein no morethan one of A7, A8 or A9 is N.E19. The compound according to any of embodiments 1-18, wherein A7 is N,A8 is C—R8 and A9 is C—R9.E20. The compound according to embodiment 19, wherein R8, R10 and R11all represent H.E21. The compound according to any of embodiments 1-18, wherein A8 is N,A7 is C—R7 and A9 is C—R9.E22. The compound according to embodiment 21, wherein R7, R10 and R11all represent H.E23. The compound according to any of embodiments 19-22, wherein R9 isselected from methyl, C₁₋₄alkoxy or cyano, wherein said methyl isoptionally substituted with C₁₋₄alkoxy or one or more fluorine.E24. The compound according to embodiment 23, wherein R9 representsC₁₋₄alkoxy and one or more of the hydrogen atoms in said C₁₋₄alkoxy arerepresented by deuterium.E25. The compound according to any of embodiments 19-22, wherein R9 isOR14, wherein R14 represents a monocyclic saturated ring moiety having4-6 ring atoms wherein one of said ring atoms is O and the others are C.E26. The compound according to any of embodiments 1-18, wherein A9 is N,A7 is C—R7 and A8 is C—R8.E27. The compound according to embodiment 26, wherein R7, R8 and R11 allrepresent H.E28. The compound according to any of embodiments 26-27, wherein R10 isselected from methyl, C₁₋₄alkoxy or cyano, wherein said methyl isoptionally substituted with C₁₋₄alkoxy or one or more fluorine.E29. The compound according to embodiment 28, wherein R10 representsC₁₋₄alkoxy and one or more of the hydrogen atoms in said C₁₋₄alkoxy arerepresented by deuterium.E30. The compound according to any of embodiments 1-17, wherein two ofA7, A8 or A9 are N.E31. The compound according to any of embodiments 1-30 having adiastereomeric excess of at least 80% such as at least 85%, such as atleast 90%, such as at least 95%.E32. The compound according to embodiment 1 selected from

-   1: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide;-   2: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(5-methyl-pyridin-2-yl)-ethyl]-amide;-   3: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-methoxy-pyridin-3-yl)-ethyl]-amide;-   4: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-methyl-pyridin-3-yl)-ethyl]-amide;-   5: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-cyano-pyridin-3-yl)-ethyl]-amide;-   6: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amide;-   7: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-ethoxy-pyridin-3-yl)-ethyl]-amide;-   8: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-ethyl-pyridin-3-yl)-ethyl]-amide;-   9: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-methoxymethyl-pyridin-3-yl)-ethyl]-amide;-   10: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(S)-1-[6-(2, 2,    2-trifluoro-ethoxy)-pyridin-3-yl]-ethyl}-amide;-   11: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    {(S)-1-[6-(2-methoxy-ethoxy)-pyridin-3-yl]-ethyl}-amide;-   12: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(2-ethoxy-pyridin-4-yl)-ethyl]-amide;-   13: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    ((S)-1-{6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethyl)-amide;-   14: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    ((S)-1-{6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethyl)-amide;-   15: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    ((S)-1-[1,3]dioxolo[4,5-b]pyridin-6-yl-ethyl)-amide;-   16: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-ethyl]-amide;-   17: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(2-ethoxy-pyrimidin-5-yl)-ethyl]-amide;-   18: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-chloro-pyridin-3-yl)-ethyl]-amide;-   19: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    {(S)-1-[6-(oxetan-3-yloxy)-pyridin-3-yl]-ethyl}-amide;-   20: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-cyanomethoxy-pyridin-3-yl)-ethyl]-amide;-   21: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;-   22: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amide;-   23: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(5-cyano-pyridin-2-yl)-2-hydroxy-ethyl]-amide;-   24; (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-methoxy-pyridin-3-yl)-ethyl]-amide;-   25: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-methyl-pyridin-3-yl)-ethyl]-amide;-   26: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide;-   27: (S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   28: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   29: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;-   30: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide;-   31: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   32: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   33: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   34: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-(1,1,2,2,2-d₅)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   35: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   36: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   37: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   38: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(6-(1,1,2,2,2-d₅)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   39: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   40: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   41: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   42: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid    [(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide;-   43: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    ((R)-2-hydroxy-1-{6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethyl)-amide;-   44:    (1S,2S)—N-[(1R)-2-hydroxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;-   45:    (1S,2S)-2-((Z)-1-Methylene-penta-2,4-dienyl)-cyclopropanecarboxylic    acid    {(R)-2-hydroxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;-   46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide;-   47:    (1S,2S)—N-[(1R)-2-methoxy-1-[6-[3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;-   48:    (1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;-   49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    {(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;-   50: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    {(S)-1-[6-(oxetan-3-yloxy)-pyridin-3-yl]-ethyl})-amide;-   51: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(S)-1-(6-ethanesulfonyl-pyridin-3-yl)-ethyl]-amide;-   52: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid    [(R)-1-(5-ethoxy-pyridin-2-yl)-2-hydroxy-ethyl]-amide;    and pharmaceutically acceptable salts of any of these compounds.    E33. A compound according to any of embodiments 1-32, for use as a    medicament.    E34. A compound according to any of embodiments 1-32, for use in    therapy.    E35. A compound according to any of embodiments 1-32, for use in the    treatment of a disease or disorder selected from Psychosis;    Schizophrenia; cognitive disorders; cognitive impairment associated    with schizophrenia; Attention Deficit Hyperactivity Disorder (ADHD);    autism spectrum disorders, Alzheimer's disease (AD): mild cognitive    impairment (MCI); age associated memory impairment (AAMI); senile    dementia; AIDS dementia; Pick's disease; dementia associated with    Lewy bodies; dementia associated with Down's syndrome; Huntington's    Disease; Parkinson's disease (PD); obsessive disorder (OCD);    traumatic brain injury; epilepsy: post-traumatic stress;    Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive    deficits associated with depression; diabetes, weight control,    inflammatory disorders, reduced angiogenesis; amyotrophic lateral    sclerosis and pain.    E36. The compound according to embodiment 35, wherein said a disease    or disorder is selected from schizophrenia; AD; ADHD; autism    spectrum disorders; PD; amyotrophic lateral sclerosis; Huntington's    disease; dementia associated with Lewy bodies and pain, E37. The    compound according to embodiment 36, wherein said disease or    disorder is selected from schizophrenia; AD; ADHD and autism    spectrum disorders.    E38. The compound according to embodiment 37, wherein said disease    or disorder is selected from negative and/or cognitive symptoms of    schizophrenia.    E39. The compound according to any of embodiments 1-32, for use    concomitantly or sequentially with a therapeutically effective    amount of a compound selected from the list consisting of    acetylcholinesterase inhibitors; glutamate receptor antagonists;    dopamine transport inhibitors; noradrenalin transport inhibitors; D2    antagonists; D2 partial agonists; PDE10 antagonists; 5-HT2A    antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodium    channel blockers and GABA signaling enhancers in the treatment of a    disease or disorder according to any of embodiments 35-38:    E40. A pharmaceutical composition comprising a compound according to    any of embodiments 1-32, and one or more pharmaceutically acceptable    carrier or excipient.    E41. The composition according to embodiment 40, which composition    additionally comprises a second compound selected from the list    consisting of acetylcholinesterase inhibitors; glutamate receptor    antagonists; dopamine transport inhibitors; norad renalin transport    inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists;    5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium;    sodium channel blockers and GABA signaling enhancers.    E42. The composition according to embodiment 41, wherein said second    compound is an acetylcholinesterase inhibitor.    E43. A kit comprising a compound according to any of embodiments    1-32, together with a second compound selected from the list    consisting of acetylcholinesterase inhibitors; glutamate receptor    antagonists; dopamine transport inhibitors; noradrenalin transport    inhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists;    5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium;    sodium channel blockers and GABA signaling enhancers.    E44. The kit according to embodiment 43, wherein said second    compound is an acetylcholinesterase inhibitor.    E45. A method for the treatment of a disease or disorder selected    from Psychosis; Schizophrenia; cognitive disorders; cognitive    impairment associated with schizophrenia; Attention Deficit    Hyperactivity Disorder (ADHD); autism spectrum disorders,    Alzheimer's disease (AD); mild cognitive impairment (MCI); age    associated memory impairment (AAMI); senile dementia; AIDS dementia;    Pick's disease; dementia associated with Lewy bodies; dementia    associated with Down's syndrome; Huntington's Disease; Parkinson's    disease (PD); obsessive-compulsive disorder (OCD); traumatic brain    injury; epilepsy; post-traumatic stress; Wernicke-Korsakoff syndrome    (WKS); post-traumatic amnesia; cognitive deficits associated with    depression; diabetes, weight control, inflammatory disorders,    reduced angiogenesis; amyotrophic lateral sclerosis and pain, which    method comprises the administration of a therapeutically effective    amount of a compound according to any of embodiments 1-32 to a    patient in need thereof.    E46. The method according to embodiment 45, wherein said disease or    disorder is selected from schizophrenia; AD; ADHD; autism spectrum    disorders; PD; amyotrophic lateral sclerosis; Huntington's disease;    dementia associated with Lewy bodies and pain.    E47. The method according to embodiment 46, wherein said disease or    disorder is selected from schizophrenia; AD; ADHD and autism    spectrum disorders.    E48. The method according to embodiment 47, wherein said treatment    comprises the treatment of negative and/or cognitive symptoms of    schizophrenia.    E49. The method according to any of embodiments 45-48, wherein said    treatment further comprises the administration of a therapeutically    effective amount of a second compound selected from the list    consisting of acetylcholinesterase inhibitors; glutamate receptor    antagonists; dopamine transport inhibitors; noradrenalin transport    inhibitors; D2 antagonists; D2 partial agonists: PDE10 antagonists;    5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium;    sodium channel blockers and GABA signaling enhancers.    E50. The method according to embodiment 49, wherein said second    compound is an acetylcholinesterase inhibitor.    E51. Use of a compound according to any of embodiments 1-32, for the    manufacture of a medicament for the treatment of a disease or    disorder selected from Psychosis; Schizophrenia; cognitive    disorders; cognitive impairment associated with schizophrenia;    Attention Deficit Hyperactivity Disorder (ADHD); autism spectrum    disorders, Alzheimer's disease (AD); mild cognitive impairment    (MCI); age associated memory impairment (AAMI); senile dementia;    AIDS dementia; Pick's disease; dementia associated with Lewy bodies;    dementia associated with Down's syndrome; Huntington's Disease;    Parkinson's disease (PD); obsessive-compulsive disorder (OCD);    traumatic brain injury; epilepsy; post-traumatic stress;    Wernicke-Korsakoff syndrome (WKS); post-traumatic amnesia; cognitive    deficits associated with depression; diabetes, weight control,    inflammatory disorders, reduced angiogenesis; amyotrophic lateral    sclerosis and pain.    E52. The use according to embodiment 51, wherein said disease or    disorder is selected from schizophrenia; AD; ADHD; autism spectrum    disorders; PD; amyotrophic lateral sclerosis; Huntington's disease;    dementia associated with Lewy bodies and pain.    E53. The use according to embodiment 52, wherein said disease or    disorder is selected from schizophrenia: AD; ADHD and autism    spectrum disorders.    E54. The use according to embodiment 53, wherein said disease is the    positive, negative and/or cognitive symptoms of schizophrenia.    E55. The use according to any of embodiments 51-54, wherein said    manufacture further comprises the use of a second compound selected    from the list consisting of acetylcholinesterase inhibitors;    glutamate receptor antagonists; dopamine transport inhibitors;    noradrenalin transport inhibitors; 02 antagonists; D2 partial    agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6 antagonists;    KCNQ antagonists; lithium; sodium channel blockers and GABA    signaling enhancers.    E56. The use according to embodiment 55, wherein said second    compound is an acetylcholinesterase inhibitor.

The compounds of the invention may exist in unsolvated as well as insolvated forms in which the solvent molecules are selected frompharmaceutically acceptable solvents such as water, ethanol and thelike. In general, such solvated forms are considered equivalent to theunsolvated forms for the purposes of this invention.

Included in this invention are also isotopically labeled compounds,which are identical to those claimed in formula [I], wherein one or moreatoms are represented by an atom of the same element having an atomicmass or mass number different from the atomic mass or mass numberusually found in nature (e.g., ²H, ³H, ¹¹C, ¹³C, ¹⁵N, ¹⁸F and the like).Particular mention is made of ²H substituted compounds i.e. compoundswherein one or more H atoms are represented by deuterium. In oneembodiment of the invention one or more of the hydrogen atoms of thecompound of formula [I] are represented by deuterium. It is recognizedthat elements are present in natural isotopic abundances in mostsynthetic compounds, and result in inherent incorporation of deuterium.However, the natural isotopic abundance of hydrogen isotopes such asdeuterium is immaterial (about 0.015%) relative to the degree of stableisotopic substitution of compounds indicated herein. Thus, as usedherein, designation of an atom as deuterium at a position indicates thatthe abundance of deuterium is significantly greater than the naturalabundance of deuterium. Any atom not designated as a particular isotopeis intended to represent any stable isotope of that atom, as will beapparent to the ordinarily skilled artisan.

In one embodiment, designation of a position as “D” in a compound has aminimum deuterium incorporation of greater than about 60% at thatposition such as greater than about 70% at that position such as greaterthan about 80% at that position such as greater than about 85% at thatposition. In a further embodiment, designation of a position as “D” in acompound has a minimum deuterium incorporation of greater than about 90%at that position such as greater than about 95% at that position such asgreater than about 97% at that position such as greater than about 99%at that position.

The compounds of the present invention have three asymmetric centerswith fixed stereochemistry indicated by the arrows below.

The compounds of the present invention can be manufactured from twochiral intermediates with one and two asymmetric centers, respectively,as illustrated by the examples below.

In this context is understood that when specifying the enantiomeric formof the intermediate; then the intermediate is in enantiomeric excess,e.g. essentially in a pure, mono-enantiomeric form. Accordingly, theresulting compounds of the invention are having a diastereomeric excessof at least 80%. One embodiment of the invention relates to a compoundof the invention having a diastereomeric excess of at least 80% such asat least 85%, such as at least 90%, preferably at least 95% or at least97% with reference to the three assymetric centers indicated above.

Dependent on the individually substituents R1-R14, the compounds of thepresent invention may furthermore have one or more additional asymmetriccenters. It is intended that any optical isomers (i.e. enantiomers ordiastereomers), in the form of separated, pure or partially purifiedoptical isomers and any mixtures thereof including racemic mixtures,i.e. a mixture of stereoisomers, which have emerged because ofasymmetric centers in any of substituents R1-R14, are included withinthe scope of the invention.

Racemic forms can be resolved into the optical antipodes by knownmethods, for example by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography of anoptically active matrix. The compounds of the present invention may alsobe resolved by the formation of diastereomeric derivatives. Additionalmethods for the resolution of optical isomers, known to those skilled inthe art, may be used. Such methods include those discussed by J. Jaques.A. Collet and S. Wilen in “Enantiomers, Racemates, and Resolutions”,John Wiley and Sons, New York (1981). Optically active compounds canalso be prepared from optically active starting materials.

Furthermore, when a double bond or a fully or partially saturated ringsystem is present in the molecule geometric isomers may be formed. It isintended that any geometric isomers, as separated, pure or partiallypurified geometric isomers or mixtures thereof are included within thescope of the invention. Likewise, molecules having a bond withrestricted rotation may form geometric isomers. These are also intendedto be included within the scope of the present invention.

Furthermore, some of the compounds of the present invention may exist indifferent tautomeric forms and it is intended that any tautomeric formsthat the compounds are able to form are included within the scope of thepresent invention.

The compounds of the present invention may be administered alone as apure compound or in combination with pharmaceutically acceptablecarriers or excipients, in either single or multiple doses. Thepharmaceutical compositions according to the invention may be formulatedwith pharmaceutically acceptable carriers or diluents as well as anyother known adjuvants and excipients in accordance with conventionaltechniques such as those disclosed in Remington: The Science andPractice of Pharmacy, 19 Edition, Gennaro, Ed., Mack Publishing Co.,Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated foradministration by any suitable route such as the oral, rectal, nasal,pulmonary, topical (including buccal and sublingual), transdermal,intracisternal, intraperitoneal, vaginal and parenteral (includingsubcutaneous, intramuscular, intrathecal, intravenous and intradermal)route, the oral route being preferred. It will be appreciated that thepreferred route will depend on the general condition and age of thesubject to be treated, the nature of the condition to be treated and theactive ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosageforms such as capsules, tablets, dragees, pills, lozenges, powders andgranules. Where appropriate, they can be prepared with coatings.

Liquid dosage forms for oral administration include solutions,emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration includesterile aqueous and nonaqueous injectable solutions, dispersions,suspensions or emulsions as well as sterile powders to be reconstitutedin sterile injectable solutions or dispersions prior to use. Othersuitable administration forms include suppositories, sprays, ointments,cremes, gels, inhalants, dermal patches, implants, etc.

In one embodiment, the compound of the present invention is administeredin an amount from about 0.001 mg/kg body weight to about 100 mg/kg bodyweight per day. In particular, daily dosages may be in the range of 0.01mg/kg body weight to about 50 mg/kg body weight per day. The exactdosages will depend upon the frequency and mode of administration, thesex, the age the weight, and the general condition of the subject to betreated, the nature and the severity of the condition to be treated, anyconcomitant diseases to be treated, the desired effect of the treatmentand other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of 0.1-1000 mg/dayof a compound of the present invention, such as 1-500 mg/day, such as1-100 mg/day or 1-50 mg/day. Conveniently, the compounds of theinvention are administered in a unit dosage form containing saidcompounds in an amount of about 0.1 to 500 mg, such as 10 mg, 50 mg 100mg, 150 mg, 200 mg or 250 mg of a compound of the present invention.

For parenteral administration, solutions of the compound of theinvention in sterile aqueous solution, aqueous propylene glycol, aqueousvitamin E or sesame or peanut oil may be employed. Such aqueoussolutions should be suitably buffered if necessary and the liquiddiluent first rendered isotonic with sufficient saline or glucose. Theaqueous solutions are particularly suitable for intravenous,intramuscular, subcutaneous and intraperitoneal administration. Thesterile aqueous media employed are all readily available by standardtechniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solution and various organic solvents. Examplesof solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc,gelatine, agar, pectin, acacia, magnesium stearate, stearic acid andlower alkyl ethers of cellulose. Examples of liquid carriers are syrup,peanut oil, olive oil, phospho lipids, fatty acids, fatty acid amines,polyoxyethylene and water. The pharmaceutical compositions formed bycombining the compound of the invention and the pharmaceuticalacceptable carriers are then readily administered in a variety of dosageforms suitable for the disclosed routes of administration.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules or tablets, eachcontaining a predetermined amount of the active ingredient, and whichmay include a suitable excipient. Furthermore, the orally availableformulations may be in the form of a powder or granules, a solution orsuspension in an aqueous or non-aqueous liquid, or an oil-in-water orwater-in-oil liquid emulsion.

If a solid carrier is used for oral administration, the preparation maybe tablet, e.g. placed in a hard gelatine capsule in powder or pelletform or in the form of a troche or lozenge. The amount of solid carriermay vary but will usually be from about 25 mg to about 1 g. If a liquidcarrier is used, the preparation may be in the form of a syrup,emulsion, soft gelatine capsule or sterile injectable liquid such as anaqueous or non-aqueous liquid suspension or solution.

Tablets may be prepared by mixing the active ingredient with ordinaryadjuvants and/or diluents followed by the compression of the mixture ina conventional tabletting machine. Examples of adjuvants or diluentscomprise: Corn starch, potato starch, talcum, magnesium stearate,gelatine, lactose, gums, and the like. Any other adjuvants or additivesusually used for such purposes such as colourings, flavourings,preservatives etc. may be used provided that they are compatible withthe active ingredients.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference in theirentirety and to the same extent as if each reference were individuallyand specifically indicated to be incorporated by reference and were setforth in its entirety herein (to the maximum extent permitted by law),regardless of any separately provided incorporation of particulardocuments made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention are to be construed to cover boththe singular and the plural, unless otherwise indicated herein orclearly contradicted by context. For example, the phrase “the compound”is to be understood as referring to various “compounds” of the inventionor particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention usingterms such as “comprising”, “having,” “including,” or “containing” withreference to an element or elements is intended to provide support for asimilar aspect or aspect of the invention that “consists of”, “consistsessentially of”, or “substantially comprises” that particular element orelements, unless otherwise stated or clearly contradicted by context(e.g., a composition described herein as comprising a particular elementshould be understood as also describing a composition consisting of thatelement, unless otherwise stated or clearly contradicted by context).

It should be understood that the various aspects, embodiments,implementations and features of the invention mentioned herein may beclaimed separately, or in any combination.

The compounds of formula I may be prepared by methods described below,together with synthetic methods known in the art of organic chemistry,or modifications that are familiar to those of ordinary skill in theart. The starting materials used herein are available commercially ormay be prepared by routine methods known in the art, such as thosemethod described in standard reference books such as “Compendium ofOrganic Synthetic Methods, Vol. I-XII” (published withWiley-Interscience). Preferred methods include, but are not limited to,those described below.

The schemes are representative of methods useful in synthesizing thecompounds of the present invention. They are not to constrain the scopeof the invention in any way.

Methods of Preparation of the Compounds of the Invention.

The compounds of the invention with formula I can be prepared fromintermediate III and II as described in Scheme 1.

If X is a hydroxyl, the carboxylic acid II and the amine Ill can becondensed to form the amide I using standard peptide coupling chemistry,e.g. as described in the textbook Synthetic Peptides A user's Guide(Edited by Gregory A. Grant, W. H. Freeman and company (1992) ISBN0-7167-7009-1) or as described in the textbook Houben-Weyl Volume E22aSynthesis of peptides (George Thiemes Verlag Stuttgart (2003) 4^(th)ed.). One example of this amide formation is the use of the couplingreagent HATU (O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate). Typically, one eq. of II is reacted with one eq.of HATU in the presence of two eq. of a tertiary amine e.g.triethylamine in a suitable solvent e.g. DMF. After a short period oftime (e.g. five minutes) this mixture is reacted with one eq. of III toform I. Another example of this amide formation uses1-hydroxybenzotriazole together with the water soluble carbodiimide EDC(CAS 25952-53-8) and triethyl amine in a suitable solvent e.g. THF.These reactions are usually performed at room temperature or between 0°C. and 50° C.

If X is a chloride (e.g. prepared from the carboxylic acid II, X═OH,using thionyl chloride) III can be reacted with II to form I in thepresence of a tertiary amine in a suitable solvent. Alternatively, thecarboxylic acid chloride (II, X═Cl) can be reacted with N-hydroxysuccinimide to produce the HOSU ester which can be isolated and thenreacted with III to produce I, Methods of Preparation of theIntermediates of the Invention.

The Intermediates of the invention with formula II are eithercommercially available or can be prepared as described in Scheme 2.

Ethyldiazoacetate can be reacted with the styrene in Scheme II toproduce the racemic-trans II ethyl ester. This ester can then behydrolyzed to racemic trans II which can then be separated into the twoenantiomers using SFC. Alternatively, racemic trans II can be resolvedinto the two enantiomers by known methods as described in the textbook“Enantiomers, Racemates and Resolutions” (J. Jaques, et al., John Wileyand sons, New York (1981)).

Another preparation of the compounds with formula II is described inScheme 3. This method has been described in detail in WO2012/037258

The benzaldehyde shown in Scheme 3 can be reacted with the anion of(Diethoxyphosphoryl)-acetic acid tert-butyl ester to produce theunsaturated ester shown. Cylopropanation followed by hydrolysis thenproduces Racemic trans II, which can be separated as described above.

The Intermediates of the invention with formula III are eithercommercially available or can be prepared as described in Scheme 4 inwhich R₆ is CH₂OH.

(R)-(+)-2-methyl-2-propanesulfinamide can be reacted with(tert-butyldimethylsilyloxy)acetaldehyde as described in the literature(Barrow, J. C. et al. Tetrahedron Letters (2001) 2051) to produce thesulfinimine shown in Scheme 4. 1,2-addition of an organometallic (e.g. aGrignard reagent or an aryllithium reagent (shown in Scheme 4) reagentto this sulfinyl imines then gives the two diastereomeric protectedamino alcohols shown in scheme 4. These isomers can be separated e.g. bysilica gel chromatography and the protecting groups are then removedunder acidic conditions.

Another method using enantiopure tert-butanesulfinamide is shown inScheme 5 (Robak, M., Herbage, M., Ellman, Chem. Rev. 2010, 110;3600-3740 and references cited herein). For simplicity, the method isonly illustrated for R₆═CH₃, but the method is not limited to R₆═CH₃.

(R)-(+)-2-methyl-2-propanesulfinamide can be reacted with a suitableketone and titanium(IV)ethoxide in a suitable solvent e.g. THF underheating conditions to produce the sulfinyl imine shown in scheme 5. Thisimine can be reduced, with some selectivity using a reducing agent (e.g.L-selectride) in a suitable solvent (e.g. THF) at a suitable temperature(e.g. −70° C.) to produce the major and the minor isomer shown in Scheme5. The major isomer can be isolated by e.g. silica gel chromatographyand the chiral auxiliary can then be removed with acid (e.g. HCl inwater to produce III).

Examples

The invention will be illustrated by the following non-limitingexamples.

Abbreviations

AcOH=acetic acid. α_(D)=specific optical rotation. Aq=Aqueous.BBr₃=boron tribromide (used as DCM solution; Aldrich 17,893-4).Boc₂O=Boc anhydride/di-t-butyl dicarbonate (e.g. Aldrich 19,913-3).Brine=saturated aqueous solution of sodium chloride. CDCl₃ deuteratedchloroform (e.g. Aldrich 225789). Celite=filter-aid. CH₃I=methyliodide/iodomethane (e.g. Aldrich 28,956-6). Cs₂CO₃=cesium carbonate(Aldrich 441902). DCM=dichloromethane. DMF=dimethyl formamide.DMSO=dimethyl sulfoxide. d₆-DMSO=deulorated dimethyl sulfoxide (e.g.Aldrich 296147). ELSD=evaporative light scattering detection.Et₃N=triethyl amine. EtOAC=ethyl acetate. 99% EtOH=absolute ethanol.Et₂O=diethyl ether, h=hours. HATU=O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexaflouruphosphate.HBTU=2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexaflourophosphate. i=iso. K₂CO₃=potassium carbonate (e.g. Aldrich20,961-9). LDA=lithium di-i-propylamide (used as aTHF/heptane/ethylbenzene solution; Fluka 62491). LC/MS=high-performanceliquid chromatography/mass spectrometer. LAH=lithium aluminium hydride(used as a 1M THF solution; Aldrich 21,277-6). MeOH=methanol,min=minutes. NaCNBH₃=sodium cyanoborohydride (Aldrich 15,615-9).NaH=sodium hydride (used as a 60% dispersion; Aldrich 45,291-2).NaOH=aqueous solution of sodium hydroxide, Pd/C=palladium-on-charcoal(e.g. Aldrich 20,569-9). PTSA=para-toluene sulfonic acid hydrate (e.g.Aldrich 40,288-5). rt=room temperature. RT=retention time. sat,NaHCO₃=saturated aqueous solution of sodium hydrogen carbonate. sat.NH₄Cl=saturated aqueous solution of ammonium chloride. SFC=supercriticalflash chromatography. TFA=trifluoroacetic acid. THF=tetrahydrofuran(dried over 4 Å molecular sieves). TLC=thin layer chromatography.

Chemical names were obtained, using the software MDL ISIS/DRAW 2.5 fromMDL information systems

Spectroscopic Methods. Method A:

LC-MS were run on a Sciex API150EX equipped with APPI-source operatingin positive ion mode. The HPLC consisted of Shimadzu LC10-ADvp LC pumps,SPD-M20A PDA detector (operating at 254 nm) and SCL-10A systemcontroller. Autosampler was Gilson 215, Column oven was a JonesChromatography 7990R and ELS detector was a Sedere Sedex 85.

LC-conditions: The column was a Waters Symmetry C-18, 4.6×30 mm, 3.5 μmoperating at 60° C. with 3.0 mL/min of a binary gradient consisting ofwater+0.05% TFA (A) and methanol+0.05% TFA (B).

Gradient:

0.01 min  17% B 0.27 min  28% B 0.53 min  39% B 0.80 min  50% B 1.07 min 59% B 1.34 min  68% B 1.60 min  78% B 1.87 min  86% B 2.14 min  93% B2.38 min 100% B 2.40 min  17% B 2.80 min  17% B Total run time: 2.8 min.

The retention times (t_(R)) are expressed in minutes based on UV-traceat 254 nm.

Method B:

LC-MS were run on Waters Acquity UPLC-MS consisting of Waters Acquityincluding column manager, binary solvent manager, sample organizer, PDAdetector (operating at 254 nM), ELS detector, and SQD-MS equipped withAPPI-source operating in positive ion mode.

LC-conditions: The column was Acquity UPLC BEH C18 1.7 μm; 2.1×50 mmoperating at 60° C. with 1.2 ml/min of a binary gradient consisting ofwater+0.05% trifluoroacetic acid (A) and acetonitrile+5% water+0.035%trifluoroacetic acid. (B)

Gradient:

0.00 min  10% B 1.00 min 100% B 1.01 min  10% B 1.15 min  10% B Totalrun time: 1.2 min.

The retention times (t_(R)) are expressed in minutes based on UV-traceat 254 nm.

Method C:

Preparative supercritical fluid chromatography (SFC) was performed on aBerger Multigram II operating at 50 mL/min at 35° C. and 100 barbackpressure using stacked injections. The column was a ChiralpakAD 5 u,250×21 mm. The eluent was CO₂ (70%) and ethanol (30%).

Method D:

Preparative supercritical fluid chromatography (SFC) was performed on aThar SFC-80 operating at 60 g/min at 35° C. and 140 bar backpressureusing stacked injections. The column was a ChiralPakAD-H (250×30 mm).The eluent was CO₂ (88%) and Ethanol (12%).

Method E:

Preparative supercritical fluid chromatography (SFC) was performed on aThar SFC-200 operating at 100 g/min at 35° C. and 140 bar backpressureusing stacked injections. The column was a ChiralPakAD-H (250×30 mm).The eluent was CO₂ (90%) and Ethanol (10%).

Method F:

Enantiomeric excess (ee) was determined on an Aurora Fusion A5 SFCsystem operating at 3 ml/min at 40° C. and 100 bar backpressure. Thecolumn was a Chiralpak AD (150×4.6 mm). The eluent was CO₂ (70%) andethanol+0.1% diethyl amine (30%).

¹H NMR spectra were recorded at 500.13 MHz on a Bruker Avance DRX-500instrument at T=303.3 K or at 600 MHz on a Bruker Avance AV-III-600instrument. Chemical shift values are expressed in ppm-values relativeto tetramethylsilane unless noted otherwise. The following abbreviationsor their combinations are used for multiplicity of NMR signals:s=singlet, d=doublet, m=multiplet and br=broad.

Preparation of Intermediates Preparation of Bromopyridines IM1:5-Bromo-2-isopropoxy-pyridine

60% NaH in oil (1.5:1, Sodium hydride:Mineral Oil, 5.20 g) was added intwo portions to isopropyl alcohol (150 mL) at room temperature under N₂.The mixture was stirred at 60° C. for 30 min. 5-bromo-2-chloropyridine(10.00 g, 51.96 mmol) was added in two portions and the mixture wasstirred at reflux 4 h and then at 80° C. overnight. The solution wasconcentrated in vacuo. Water (50 mL) and EtOAc (50 mL) was added and thelayers were separated. The aqueous layer was extracted with EtOAc (50mL). The combined organic layers were washed with brine, dried overMgSO₄, filtered and the solvent was removed in vacuo. The crude productwas subjected to flash chromatography (silica, 0-50% EtOAc in heptanes)to give the title compound as a clear oil (8.74 g, 78%). ¹H NMR (600MHz, DMSO) δ 8.17 (s, 1H), 7.61 (dd, 1H), 6.59 (d, 1H), 5.23 (m, 1H),1.33 (s, 6H).

IM2: 5-Bromo-2-(2, 2, 2-trifluoro-ethoxy)-pyridine

Prepared analogously to IM1 to give the title compound as a colorlessliquid (2.78 g, 54%) sufficiently pure for the next step.

IM3: 5-Bromo-2-propoxy-pyridine

Potassium tert-butoxide (1.85 g, 16.5 mmol) was added to a mixture of5-bromo-2-chloropyridine (2.89 g, 15.0 mmol) and 1-propanol (1.230 mL,16.5 mmol) in THF (15 mL). The reaction mixture was heated at 120° C.for 30 minutes in a microwave reactor. The mixture was poured into amixture of water (50 mL) and EtOAc (100 mL). The organic layer waswashed with brine, dried over MgSO₄ and evaporated to dryness. Flashchromatography (silica, 0-20% EtOAc in heptanes) gave the title compoundas a yellow oil (3.13 g, 97%) sufficiently pure for the next step.

IM4: 5-Bromo-2-(2,2,2-d₃)-ethoxy-pyridine

Prepared analogously to IM3 using commercially available2,2,2-d₃-ethanol (Sigma-Aldrich, catalog no 329347) to give the titlecompound as a colorless oil (2.53 g, 82%) sufficiently pure for the nextstep.

IM5: 5-Bromo-2-(1,1,2,2,2-d₅)-ethoxy-pyridine

Prepared analogously to IM3 using commercially available1,1,2,2,2-d₅-ethanol (Sigma-Aldrich, catalog no 489336) to give thetitle compound as a colorless oil (1.16 g, 87%) sufficiently pure forthe next step.

IM6: 5-Bromo-2-(1,1-d₂)-ethoxy-pyridine

Prepared analogously to IM3 using commercially available 1,1-d₂-ethanol(Sigma-Aldrich, catalog no 347434) to give the title compound as acolorless oil (2.61 g, 85%) sufficiently pure for the next step.

IM7: 5-Bromo-2-(2-methoxy-ethoxy)-pyridine

2-Methoxyethanol (5.12 mL, 65.0 mmol) was dissolved in 1,4-dioxane (125mL). Potassium tert-butoxide (7.00 g, 62.4 mmol) was added under N₂. Themixture was stirred for 10 minutes. 5-Bromo-2-chloropyridine (10.0 g,52.0 mmol) was added and the resulting mixture was refluxed for 2 hours.The mixture was poured into brine and extracted with EtOAc. The organiclayer was washed with brine, dried over MgSO₄ and evaporated to dryness.Purification by flash chromatography (silica, heptanes/EtOAc 4:1) gavethe title compound as a colorless oil (8.74 g, 73%) sufficiently purefor the next step.

IM8: 5-Bromo-2-methoxymethyl-pyridine

To a solution of 5-bromopyridine-2-carbaldehyde (5.00 g, 26.9 mmol)dissolved in a mixture of ethanol (75 mL) and THF (25 mL) was addedsodium borohydride (0.407 g, 10.8 mmol) in small portions. After 45minutes 0.5 mL water was added and the mixture and evaporated todryness. The oily residue was subjected to flash chromatography (silica,EtOAc/EtOH/Et3N 90:5:5) to give (5-bromo-pyridin-2-yl)-methanol (4.81 g,86%) as pale-yellow oil. A solution of this(5-bromo-pyridin-2-yl)-methanol (4.80 g, 23.0 mmol) in DMF (25 mL) wasadded drop wise over 5 minutes to a slurry of sodium hydride (1.10 g,27.6 mmol) in DMF (50 mL) at 0° C. under N₂. The mixture was stirred for15 minutes before the drop wise addition of a solution of methyl iodide(1.57 mL, 25.3 mmol) in DMF (25 mL). The mixture was allowed to reachroom temperature and was then stirred overnight. The mixture was pouredinto brine and extracted with EtOAc. The combined organic layers werethoroughly washed with brine, dried over MgSO₄ and evaporated to drynessto give the title compound as a yellow oil (4.77 g, 98%) sufficientlypure for the next step.

IM9: 5-Bromo-2-cyclobutoxy-pyridine

Prepared analogously to IM3 using commercially available cyclobutanol togive the title compound as a clear oil (2.72 g, 80%) sufficiently purefor the next step.

IM10: 5-Bromo-2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridine

To a solution of 5-bromo-2-chloropyridine (10 g, 52.1 mmol) in 100 mL ofDMF was added commercially available (R)-(−)-3-hydroxytetrahydrofuran(6.87 g, 78.1 mmol) and Cs₂CO₃ (33.85 g, 0.104 mol), the resultingmixture was heated 90° C. for 36 hours. The solvent was concentrated andthe residue was extracted with EtOAc (500 ml), washed with water (200ml). The organic layer was dried over Na₂SO₄, concentrated and purifiedby chromatography on silica gel (eluting with Petrol ether: EtOAc=100:1)to afford 5-Bromo-2-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridine (5.9 g.yield: 47%) as a solid. ¹HNMR (CDCl₃ 400 MHz): δ8.15 (d, J=2.4 Hz, 1H),7.61-7.64 (m, 1H), 6.64 (d, J=8.8 Hz, 1H), 5.47-5.50 (m, 1H), 3.85-4.02(m, 4H), 2.07-2.28 (m, 2H). [α]_(D) ²⁰=+18.5 (C=0.189, CHCl₃).

IM11: 5-Bromo-2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridine

Prepared analogously to IM10 using commercially available(S)-(+)-3-hydroxytetrahydrofuran to afford5-Bromo-2-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridine

(9.62 g, yield: 51%) as a solid. ¹HNMR (CDCl₃400 MHz): δ8.16 (d, J=2.4Hz, 1H), 7.62-7.65 (m, 1H), 6.64-6.66 (m, 1H), 5.48-5.52 (m, 1H),3.99-4.03 (m, 2H), 3.86-3.97 (m, 2H), 2.20-2.29 (m, 1H), 2.08-2.15 (m,1H). [α]_(D) ²⁰=−20.7 (C=0.21, CHCl₃).

IM12: 5-Bromo-2-(tetrahydro-pyran-4-yloxy)-pyridine

Prepared analogously to IM3 using commercially availabletetrahydro-4-pyranol to give the title compound sufficiently pure forthe next step.

IM13: 6-Bromo-[1,3]dioxolo[4,5-b]pyridine

To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol,commercially available, CAS 34206-49-0) in NMP (100 mL) was added K₂CO₃(21.97 g, 158 mmol) and dibromo methane (10.97 g, 63.16 mmol). Thereaction mixture was heated to 90° C. for 16 h. EtOAc was added and thesalts were filtered off. Water was added, the phases were separated andthe aq layer was extracted with more ethyl acetate. The combined organiclayers was dried over anhydrous Na₂SO₄ and concentrated under vacuo toget the crude compound. The crude compound was purified by silica gelchromatography (eluent 5% ethyl acetate in petrol ether). Yield of6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2:2 g (21%) pure by ¹H NMR (400 MHz,DMSO) δ7.71 (d, 1H, J=2 Hz), 7.55 (d, 1H, J=2 Hz), 6.20 (s, 2H). Mp69-71 C.

IM14: 7-Bromo-2, 3-dihydro-[1,4]dioxino[2,3-b]pyridine

To a suspension of 5-Bromo-pyridine-2,3-diol (10.0 g, 52.63 mmol,commercially available, CAS 34206-49-0) in DMF (150 mL) was added K₂CO₃(21.78 g, 158 mmol) and 1,2-dibromo ethane (11.87 g, 63.2 mmol). Thereaction mixture was heated to 100° C. for 5 h. The reaction mixture wascooled to rt and poured into ice cold water EtOAc was added and thephases were separated and the aq layer was extracted with more ethylacetate. The combined organic layers was dried over anhydrous Na₂SO₄ andconcentrated under vacuo to get the crude compound. The crude compoundwas purified by silica gel chromatography (eluent 10% ethyl acetate inpetrol ether). Yield of 6-Bromo-[1,3]dioxolo[4,5-b]pyridine 2.2 g (18%)pure by ¹H NMR (400 MHz, DMSO) δ 7.85 (d, 1H, J=2 Hz), 7.59 (d, 1H, J=2Hz), 4.41 (m, 2H), 4.27 (m, 2H).

Acetylation of Pyridines IM15: 1-(6-Chloro-pyridin-3-yl)-ethanone

A round bottomed flask was charged with 5-bromo-2-chloropyridine (5.30g, 27.6 mmol) in THF under N₂ and cooled at 0° C. A solution of 1 Miso-propylmagnesiumchloride-lithium chloride complex in THF (40 mL) wasadded drop wise over 15 min. After 70 min N-methoxy-N-methylacetamide(4.1 mL, 38 mmol) was added drop wise. After stirring for 5 min at 0° C.the cooling bath was removed. The mixture was left stirring overnightand was then quenched by the addition of 100 mL saturated aqueous NH₄Clsolution. The mixture was extracted with 3×100 mL EtOAc. The combinedorganic layers were washed with water followed by brine and dried overMgSO₄. Evaporation of the volatiles at 80° C., 10 mbar for 1 h gave thetitle compound (3.596 g, 84) sufficiently pure for the next step.

IM16: 1-(6-Iso-propoxy-pyridin-3-yl)-ethanone

A round-bottomed flask was charged with 5-bromo-2-iso-propoxypyridine(IM1) (5.00 g, 23.1 mmol) in THF (100) under N₂ and cooled in anacetone/dry-ice bath to −66° C. (internal temperature). A solution of2.5 M n-butyllithium in hexane (10.1 mL, 25.3 mmol) was added drop wiseover 10 minutes at keeping the internal temperature below −55° C. Themixture was stirred at −65° C. for 15 minutes.N-methoxy-N-methylacetamide (3.07 mL, 28.9 mmol) dissolved in THF (10mL) was then added drop wise over 10 minutes while keeping the internaltemperature below −65° C. After stirring for 1 h the mixture was allowedto reach room temperature. The mixture was poured into saturated aqueousNH₄Cl solution and extracted with EtOAc. The combined organic layerswere washed with brine, dried over MgSO₄ and evaporated to dryness.Flash chromatography (silica, heptanes/EtOAc 4:1) gave the titlecompound as a colorless oil (3.20 g, 77%) sufficiently pure for the nextstep.

IM17: 1-(6-Methoxymethyl-pyridin-3-yl)-ethanone

Prepared analogously to IM16 from IM8 to give the title compound as acolorless liquid (0.379 g, 17%) sufficiently pure for the next step.

IM18: 1-[6-(2,2,2-Trifluoro-ethoxy)-pyridin-3-yl]-ethanone

Prepared analogously to IM16 from IM2 to give the title compound as acolorless liquid (1.234 g, 48%) sufficiently pure for the next step.

IM19: 1-[6-(2-Methoxy-ethoxy)-pyridin-3-yl]-ethanone

Prepared analogously to IM16 from IM7 to give the title compound as acolorless liquid (2.13 g, 57%) sufficiently pure for the next step.

IM20: 1-(2-Ethoxy-pyridin-4-yl)-ethanone

Prepared analogously to IM16 from commercially available4-bromo-2-ethoxy-pyridine, Synchem OHG catalog no CT091 to give thetitle compound as a colorless liquid (1.20 g, 49%) sufficiently pure forthe next step.

IM21: 1-[1,3]Dioxolo[4,5-b]pyridin-6-yl-ethanone

A round-bottomed flask was charged with6-Bromo-[1,3]dioxolo[4,5-b]pyridine IM13 (1.74 g, 8.61 mmol) in DMF (25ml) under N₂ and tributyl(1-ethoxyvinyl)tin (3.65 ml, 10.8 mmol) wasadded. Tetrakistriphenylphosphinepalladium(0) (0.50 g, 0.43 mmol) wasadded and the solution was stirred at 65° C. overnight. The mixture wasadded to water and EtOAc and the phases were separated. The org phasewas washed with brine, dried (MgSO4) filtered and was rotovaped. Theresidue was dissolved in THF (100 ml), and a mixture of water (15 ml)and conc. HCl (2.5 ml) was added and the solution was stirred at rt 5min. The solution was added to brine and sat NaHCO3 solution was addeduntil the solution was slightly alkaline. The org Phase was extractedwith EtOAc and the phases were separated. The org phase was washed withbrine, dried (MgSO4) filtered and was rotovaped. The residue wasredissolved in THF (10 ml) EtOAc (20 ml) and heptanes (20 mil). Themixture was concentrated until 25 ml remained and cooled in ice. A solidprecipitated and was collected by filtration. Yield: 0.942 g (66%) ofIM21. 1H-NMR (500 MHz, DMSO) δ 8.47 (s, 1H), 8.54 (s, 1H), 6.27 (s, 2H),2.53 (s, 3H).

IM22: 1-(2,3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-ethanone

Prepared analogously to IM21 from with7-Bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (3.00 g, 13.9 mmol) togive the title compound as a white powder (1.84 g, 74%). 1H-NMR (500MHz, DMSO) δ 8.47 (s, 1H), 8.54 (s, 1H), 6.27 (s, 2H), 2.53 (s, 3H).

IM23: 1-(6-Ethyl-pyridin-3-yl)-ethanone

A dry round bottomed flask was charged with1-(6-chloro-3-pyridinyl)-1-ethanone (IM15) (3.596 g, 23.11 mmol) and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (1.694 g,2.315 mmol) in THF (100 mL) under N₂. A 1 M solution of diethyl zinc inhexane (35 mL, 35 mmol) was added drop wise to this mixture followed byN,N-dimethylaminoethanol (0.50 mL, 5.0 mmol). The mixture was heated toreflux for 30 minutes. The mixture was cooled to room temperature andthen quenched by the addition of saturated aqueous NH₄Cl solution (100mL). The mixture was filtered through a plug of celite. The aqueouslayer was extracted with EtOAc (3×100 mL). The combined organic layerswere washed with water, brine and then dried over Mg₂SO₄. FlashChromatography (120 g silica, 0-40% EtOAc in heptanes) gave the titlecompound as a yellow oil (0.699 g, 20%) sufficiently pure for the nextstep.

Preparation of Chiral Amines

Chiral amines were made, if not commercially available, according towell-described procedure for either 1,2-stereoselective reduction ofsulfinyl imines or 1,2-stereoselective addition of organometallicreagents to sulfinyl imines. These methods have been described byChellucci, G., Baldino, S., Chessa, S., Pinna, G., Soccolini, S.,Tetrahedron Asymmetry 2006, 17, 3163-3169, Evans, J., Ellman, J., J.Org. Chem. 2003, 68, 9948-9957 and Robak, M., Herbage, M., Ellman, J.,Chem. Rev. 2010, 110, 3600-3740 and references cited herein.

IM24: (S)-1-(6-isopropoxy-pyridin-3-yl)-ethylamine)

Step 1: Formation of Sulfinyl Imine:

1-(6-Iso-propoxy-pyridin-3-yl)-ethanone IM16 (3.20 g, 17.8 mmol) wasdissolved in THF (55 mL) under N₂. R(+)-2-methyl-2-propanesulfinamide(2.21 g, 18.2 mmol) and titanium(IV)ethoxide (7.40 mL, 35.7 mmol) wasadded. The mixture was refluxed for 24 hours. The mixture was allowed toreach room temperature. The mixture was diluted with EtOAc (200 mL) andpoured into ice/brine. The resulting slurry was filtered through Celite.The organic layer was washed with brine, dried over MgSO₄ and evaporatedto dryness. Flash chromatography (silica, heptanes/EtOAc 2:1) gave(R)-2-methyl-propane-2-sulfinic acid[1-(6-isopropoxy-pyridin-3-yl)-ethylidene]-amide (4.04 g, 80%) as ayellow oil sufficiently pure for the next step.

Step 2: Reduction of the Imine:

A round-bottomed flask was charged with (R)-2-methyl-propane-2-sulfinicacid [1-(6-iso-propoxy-pyridin-3-yl)-ethylidene]-amide (4.00 g, 14.2mmol) in THF (50 mL) under N₂ and cooled to −66° C. (internaltemperature). A 1.00 M solution of L-Selectride in THF (29.0 mL, 29.0mmol) was added drop wise over 15 minutes. The mixture was stirred at−70° C. for 1 hour. The cold mixture was poured into saturated aqueousNH₄Cl solution. The mixture was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄ and evaporatedto dryness. Flash chromatography (silica, EtOAc) gave(R)-2-methyl-propane-2-sulfinic acid[(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amid (2.91 g, 72%) as acolorless powder. Diastereomeric excess >95% based on ¹H NMR.

Step 3: Removal of Chiral Auxiliary:

(R)-2-Methyl-propane-2-sulfinic acid[(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide (2.90 g, 10.2 mmol) wasdissolved in methanol (48 mL). A mixture of 12.0 M HCl in water (4.25mL) and water (4.25 mL) was added drop wise over 3 minutes. The mixturewas stirred at room temperature overnight. The mixture was evaporated todryness. The oily residue was subjected to flash chromatography (silica,EtOAc/EtOH/triethylamine 90:5:5) on a short column to give(S)-1-(6-isopropoxy-pyridin-3-yl)-ethylamine IM24 (1.71 g, 93%) as apale-yellow oil sufficiently pure for the next step. The overall yieldfrom 1-(6-isopropoxy-pyridin-3-yl)-ethanone IM16 was 54%.

IM25: (S)-1-(6-Ethyl-pyridin-3-yl-ethylamine

Prepared analogously to IM24 from IM23 to give the title compoundsufficiently pure for the next step.

IM26: (S)-1-(6-Methoxymethyl-pyridin-3-yl)-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM27 (S)-1-[6-(2, 2,2-Trifluoro-ethoxy)-pyridin-3-yl]-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM28: (S)-1-[6-(2-Methoxy-ethoxy)-pyridin-3-yl]-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM29: (S)-1-(2-Ethoxy-pyridin-4-yl)-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM30: (S)-1-{6-[(S)-(Tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM31: (S)-1-{6-[(R)-(Tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM32: (S)-1-[1,3]Dioxolo[4, 5-b]pyridin-6-yl-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM33: (S)-1-(2, 3-Dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM34: (S)-1-(2-Ethoxy-pyrimidin-5-yl)-ethylamine

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM35: 2-[5-((S)-1-Amino-ethyl)-pyridin-2-yloxy]-ethanol

Prepared analogously to IM24 to give the title compound sufficientlypure for the next step.

IM36: (R)-2-Amino-2-(6-propoxy-pyridin-3-yl)-ethanol

Step 1:

A 1.7 M solution of tert-butyllithium in pentane (15.2 mL, 25.8 mmol)was added drop wise to a stirring solution of 5-bromo-2-propoxypyridineIM3 (2.54 g, 11.8 mmol) dissolved in dry THF (29.4 mL) at −78° C. underAr. The solution was subsequently stirred at this temperature for 30min. A solution of (R)-2-methyl-propane-2-sulfinic acid[2-(tert-butyl-dimethyl-silanyloxy)ethylidene]-amide IM49 (3.26 g, 11.8mmol) in dry THF (15 mL) was then added drop wise at −78° C. and thesolution was stirred at this temperature for 30 min. The cooling bathwas removed and the mixture was allowed to reach room temperatureovernight. The mixture was quenched with saturated aqueous NH₄Clsolution (75 mL) and EtOAc (150 mL). The phases were separated and theorganic layer was washed with brine and then dried over MgSO₄. Flashchromatography (silica, 10-100% EtOAc in heptanes) gave(R)-2-Methyl-propane-2-sulfinic acid[(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide,the fastest eluding isomer, as a clear oil (2.33 g, 48%) sufficientlypure for the next step. Diastereomeric excess >95% based on ¹H NMR.

Step 2:

A 2.00 M solution of hydrogen chloride in diethyl ether (28 mL, 56 mmol)was added to a stirred solution of[(R)-2-(tert-butyl-dimethyl-silanyloxy)-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide(2.33 g, 5.62 mmol) dissolved in MeOH (11 mL) at 0° C. under Ar. Afterthe addition was completed the cooling bath was removed and the solutionwas stirred at room temperature overnight. The mixture was thenevaporated to dryness and the residue was suspended in methylenechloride and transferred to a short silica gel column. After eludingwith EtOAc:EtOH:Et₃N (90:5:5)(R)-2-Amino-2-(6-propoxy-pyridin-3-yl)-ethanol, IM36, was obtained as anoil (0.813 g, 74%). The overall yield from 5-bromo-2-propoxypyridine IM3was 36%.

¹H NMR (600 MHz, CDCl₃) δ 8.61 (s, 1H), 8.60 (dd, 1H), 7.71 (d, 1H),4.22 (t, 2H), 4.06 (m, 1H), 3.72 (m, 1H), 3.60 (m, 1H), 1.78 (m, 2H),1.24 (m, 1H), 1.02 (m, 4H).

IM37: (R)-2-Amino-2-(6-isopropoxy-pyridin-3-yl)-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step (1.07 g, 36% overall yield from IM1).

IM38: (R)-2-Amino-2-(6-ethoxy-pyridin-3-yl)-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step (0.360 g, 35% overall yield from commerciallyavailable 5-bromo-2-ethoxy-pyridine, Apollo catalog no OR13065).

IM39: (R)-2-Amino-2-(6-(1,1,2,2,2-d₅)-ethoxy-pyridin-3-yl)-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step (0.500 g, 22% overall yield from IM5).

IM40: (R)-2-Amino-2-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step (0.647 g, 30% overall yield from IM4).

IM41: (R)-2-Amino-2-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step (0.380 g, 18% overall yield from IM6).

IM42:(R)-2-Amino-2-{6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step.

IM43:(R)-2-Amino-2-{6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step.

IM44: (R)-2-Amino-2-(6-cyclobutoxy-pyridin-3-yl)-ethanol

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step.

IM45: (R)-2-Amino-2-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-etheno

Prepared analogously to IM36 to give the title compound sufficientlypure for the next step.

Preparation of Carboxylic Acids IM46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid

Commercially available, racemic trans 2-phenyl-cyclopropanecarboxylicacid (Sigma-Aldrich, catalog no P22354) was subjected to chiral SFCseparation, method C to give IM46 as an oil that slowly solidified uponstanding. Enantiomeric purity 95% ee (Method F). Specific opticalrotation+300.9° [α]_(D) ²⁰ (C=1% EtOH). (Lit: +389° [α]_(D) ²⁰ (C=0.61,CHCl₃) Kozikowski et al., J. Med. Chem. 2009, 52, 1885-1902), (Lit:+311.7° [α]_(D) ²⁰ (C=1.776, EtOH) Walborsky et al., Tetrahedron 1964,20, 1695-1699.)

IM47: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid

Step 1:

A round-bottomed flask was charged with 3-fluorostyrene (13.0 g, 0.107mol) in anhydrous methylene chloride (130 mL). To this mixture was addedrhodium acetate dimer (1.30 g, cat amount). A solution ofethyldiazoacetate (33.28 g, 0.291 mol) in anhydrous methylene chloride(130 mL) was added to the reaction via a syringe pump over 5 h andstirred at room temperature for 1 h in darkness. The reaction mixturewas filtered through a plug of celite, which was washed with waterfollowed by brine. The organic layer was dried over Na₂SO₄ andevaporated to dryness. Flash chromatography (silica, EtOAc/petroleumether 1:9) gave rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid ethyl ester (13.0 g, 59%) as a colorless liquid sufficiently purefor the next step.

Step 2:

To a solution of rac-trans 2-(3-fluoro-phenyl)-cyclopropanecarboxylicacid ethyl ester (13.0 g, 0.062 mol) in MeOH (310 mL) was added asolution of KOH (35.0 g, 0.625 mol) in MeOH (150 mL) at 0° C. Afteraddition of the base the reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was poured into water andextracted with methylene chloride (2×50 mL). The aqueous layer wasacidified with 10% HCl. The resulting mixture was extracted withmethylene chloride (2×150 mL). The combined organic layers were driedover Na₂SO₄ and evaporated to dryness to giverac-trans-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid as colorlesscrystals (9.5 g, 85%). Separation of the isomers by chiral SFC (MethodD) gave the title compound(1S,2S)-2-(3-fluoro-phenyl)-cyclopropanecarboxylic acid IM47 ascolorless crystals (3.27 g, 17% overall yield from 3-fluorostyrene)sufficiently pure for the next step. Specific optical rotation+263.4°[α]_(D) ²⁰ (C=1% MeOH)

IM48: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid

Prepared analogously to IM48 using SFC method E to give the titlecompound sufficiently pure for the next step (3.1 g, 13% overall yieldfrom 4-fluorostyrene). Specific optical rotation+263.2° [α]_(D) ²⁰ (C=1%MeOH)

Other Intermediates IM49: (R)-2-Methyl-propane-2-sulfinic acid[2-(tert-butyl-dimethyl-silanyloxy)-ethylidene]-amide

(R)-(+)-2-methyl-2-propanesulfinamide (8.70 g, 71.8 mmol), pyridiniump-toluenesulfonate (0.902 g, 3.59 mmol) and MgSO₄ (43.2 g, 359 mmol) wassuspended in methylene chloride (25 mL). A solution of(tert-butyldimethylsilyloxy)acetaldehyde (25.0 g, 144 mmol) dissolved inmethylene chloride (10 m L) was added drop wise at room temperature. Thereaction was stirred at room temperature overnight. The mixture wasevaporated to dryness. Flash chromatography (silica, EtOAc/heptanes 1:4)gave the title compound as an oil that slowly solidified upon standing(18.3 g, 92%) sufficiently pure for the next, step.

Example 1: Preparation of Example Compounds of the Invention Compound 1:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide

Trans-2-phenyl-1-cyclopropanecarboxylic acid IM46 (0.590 g, 3.64 mmol)was dissolved in DMF (15.0 mL).N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uroniumhexafluorophosphate (1.38 g, 3.63 mmol) was added. Triethylamine (1.10mL, 7.89 mmol) was then added and the mixture was stirred for 15 minutesat room temperature. This mixture was added drop wise to a solution of(S)-1-(6-isopropoxy-pyridin-3-yl)-ethylamine IM24 (0.655 g, 3.63 mmol)dissolved in DMF (15.0 mL) over 2 minutes. The mixture was stirred atroom temperature over night. The mixture was evaporated to dryness. Theresidue was transferred to a silica gel column and eluded withEtOAc/heptanes 1:1 to give Compound 1 as a solid. This solid wasdissolved in EtOAc (50 mL) and to this solution was slowly addedheptanes (50 mL). The mixture was concentrated to approx. 25 mL in vacuoand this solution was cooled in an ice/water bath. A white precipitateformed. The solids was collected by filtration and dried in vacuo togive the title compound as colorless crystals (0.794 g, 67%). LC-MS(m/z) 325.4 (MH+), t_(R)=1.51 min (method A). ¹H NMR (500 MHz, DMSO) δ8.57-8.50 (m, 1H), 8.06 (br s, 1H), 7.65-7.57 (m, 1H), 7.30-7.24 (m,2H), 7.20-7.14 (m, 1H), 7.10 (d, J=7.5 Hz, 2H), 6.69 (d, J=8.5 Hz, 1H),5.25-5.16 (m, 1H), 4.98-4.88 (m, 1H), 2.24-2.15 (m, 1H), 1.94-1.88 (m,1H), 1.41-1.32 (m, 4H), 1.26 (d, J=6.2 Hz, 6H), 1.20 (ddd, J=8.5, 6.1,4.1 Hz, 1H). Diastereomeric excess >95% based on ¹H NMR.

Compound 2: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(5-methyl-pyridin-2-yl)-ethyl]-amide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.709 g,3.70 mmol) and hydroxybenzotriazole (0.667 g, 4.93 mmol) were added to astirred mixture of IM46 (0.60 g, 3.70 mmol) and commercially available(S)-1-(5-methyl-pyridin-2-yl)-ethylamine hydrochloride (Supplier NetchemInc., Catalog No 528193) (0.426 g, 2.47 mmol) andN,N-diisopropylethylamine (0.859 ml, 4.93 mmol) in THF (25 ml). Thesolution was stirred at rt overnight. Water was added and the mixturewas extracted with EtOAc (3×80 ml). The combined organic phases werewashed with brine, dried over MgSO4, filtered and the solvent wasevaporated of in vac. The crude product was purified by silica gelchromatography (EtOAc in heptanes 1:1). Yield of Compound 2: 110 mg(16%). LC-MS (m/z) 281.1 (MH+), t_(R)=0.91 min (method A).

Compound 3: (S, 2S)-2-Phenyl-cyclopropanecarboxylicacid-[(S)-1-(6-methoxy-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and commercially available(S)-1-(6-methoxy-pyridin-3-yl)-ethylamine (Supplier Netchem Inc.,Catalog No 517706). Yield=0.88 g (66%). ¹H NMR (500 MHz, DMSO) δ 8.55(d, 1H), 8.10 (s, 1H), 7.63 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.10(d, 2H), 6.78 (d, 1H), 4.93 (m, 1H), 3.72 (s, 3H), 2.21 (m, 1H), 1.90(m, 1H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 297.4 (MH+), t_(R)=1.36min (method A).

Compound 4: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-methyl-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and commercially available(S)-1-(6-methyl-pyridin-3-yl)-ethylamine (Supplier Netchem Inc., CatalogNo 519526). Yield=0.27 g (21%). ¹H NMR (600 MHz, DMSO) δ 8.61 (d, 1H),8.37 (s, 1H), 7.57 (d, 1H), 7.26 (m, 2H), 7.16 (m, 2H), 7.09 (d, 2H),4.92 (m, 1H), 2.41 (s, 3H), 2.19 (m, 1H), 1.91 (m, 1H), 1.36 (m, 4H),1.20 (m, 1H). LC-MS (m/z) 281.2 (MH+), t_(R)=0.86 min (method A).

Compound 5: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-cyano-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 2 using IM46 and commercially available5-((S)-1-amino-ethyl)-pyridine-2-carbonitrile hydrochloride (SupplierNetchem Inc., Catalog No 549493). Yield=0.104 g (20%). %). ¹H NMR (600MHz, DMSO) δ 8.76 (d, 1H), 8.71 (s, 1H), 8.02 (d, 1H), 7.94 (d, 1H),7.29 (m, 2H), 7.19 (m, 1H), 7.12 (d, 2H), 5.03 (m, 1H), 2.21 (m, 1H),1.92 (m, 1H), 1.40 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z)292.0 (MH+), t_(R)=1.31 min (method A).

Compound 6: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 2 using IM46 and commercially available(S)-1-(6-trifluoromethyl-pyridin-3-yl)-ethylamine hydrochloride.(Supplier Netchem Inc., Catalog No 517662). Yield=0.33 g (55%). %). ¹HNMR (500 MHz, DMSO) δ 8.77 (d, 1H), 8.72 (s, 1H), 7.99 (d, 1H), 7.88 (d,1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.13 (d, 2H), 5.05 (m, 1H), 2.20 (m,1H), 1.93 (m, 1H), 1.41 (d, 3H), 1.37 (m, 1H), 1.23 (m, 1H). LC-MS (m/z)335.2 (MH+), t_(R)=1.59 min (method A).

Compound 7: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-ethoxy-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 2 using IM46 and commercially available(S)-1-(6-ethoxy-pyridin-3-yl)-ethylamine hydrochloride (Supplier SialGmbh, Catalog No 528261-HCl, Lot no LNA098). Yield=0.30 g (39%). ¹H NMR(500 MHz, DMSO) δ 8.54 (d, 1H), 8.08 (s, 1H), 7.62 (d, 1H), 7.27 (m,2H), 7.16 (m, 1H), 7.12 (d, 2H), 6.73 (d, 1H), 4.92 (m, 1H), 4.25 (q,2H), 2.20 (m, 1H), 1.91 (m, 1H), 1.35 (m, 4H), 1.30 (t, 3H), 1.19 (m,1H). LC-MS (m/z) 311.4 (MH+), t_(R)=1.45 min (method A).

Compound 8: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-ethyl-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and IM25. Yield=0.44 g(65%). ¹H NMR (500 MHz, DMSO) δ 8.51 (d, 1H), 8.41 (s, 1H), 7.27-7.14(m, 4H), 7.10 (d, 2H), 4.96 (m, 1H), 2.72 (q, 2H), 2.20 (m, 1H), 1.92(m, 1H), 1.38 (m, 4H), 1.21 (m, 4H). LC-MS (m/z) 295.1 (MH+), t_(R)=0.90min (method A).

Compound 9: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-methoxymethyl-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and IM26. Yield=0.18 g(40%). ¹H NMR (500 MHz, DMSO) δ 8.63 (d, 1H), 8.10 (s, 1H), 7.71 (d,1H), 7.37 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 4.97 (m,1H), 3.37 (s, 3H), 2.21 (m, 1H), 1.93 (m, 1H), 1.39 (m, 4H), 1.20 (m,1H). LC-MS (m/z) 311.3 (MH+), t_(R)=0.98 min (method A).

Compound 10: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(S)-1-[6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-ethyl}-amide

Prepared analogously to Compound 1 using IM46 and IM27. Yield=0.695 g(50%). ¹H NMR (500 MHz, DMSO) δ 8.62 (d, 1H), 8.12 (s, 1H), 7.73 (d,1H), 7.27 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.95 (d), 4.97 (m, 3H),2.20 (m, 1H), 1.91 (m, 1H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z)365.3 (MH+), t_(R)=1.78 min (method A).

Compound 11: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(S)-1-[6-(2-methoxy-ethoxy)-pyridin-3-yl]-ethyl}-amide

Prepared analogously to Compound 1 using IM46 and IM28. Yield=0.758 g(30%). ¹H NMR (500 MHz, DMSO) δ 8.57 (d, 1H), 8.08 (s, 1H), 7.65 (d,1H), 7.26 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.78 (d, 1H), 4.92 (m,2H), 4.32 (m, 2H), 3.62 (m, 2H), 3.27 (s, 3H), 2.20 (m, 1H), 1.89 (m,1H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 341.0 (MH+), t_(R)=1.33 min(method A).

Compound 12: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(2-ethoxy-pyridin-4-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and IM29. Yield=0.11 g(48%). ¹H NMR (500 MHz, DMSO) δ 8.55 (d, 1H), 8.06 (s, 1H), 7.30 (m,2H), 7.19 (m, 1H), 7.14 (m, 2H), 6.90 (d, 1H), 6.67 (d, 1H), 4.88 (m,1H), 4.26 (m, 2H), 2.20 (m, 1H), 1.96 (m, 1H), 1.40-1.27 (m, 7H), 1.22(m, 1H). LC-MS (m/z) 311.4 (MH+), t_(R)=1.36 min (method A).

Compound 13: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-{6-[(S)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl]-ethyl}-amide

Prepared analogously to Compound 1 using IM46 and IM30. Yield=0.983 g(62%). 1H-NMR (500 MHz, DMSO) δ8.55 (d, 1H), 8.09 (s, 1H), 7.64 (d, 1H),7.27 (m, 2H), 7.16 (m, 1H), 7.11 (d, 2H), 6.78 (d, 1H), 5.48 (m, 1H)4.96 (m, 1H), 3.92 (m, 1H), 3.85 (m, 1H), 3.74 (m, 2H), 2.21 (m, 2H),1.95 (m, 2H), 1.37 (m, 4H), 1.19 (m, 1H). LC-MS (m/z) 353.3 (MH+),t_(R)=1.45 min (method A).

Compound 14: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-{6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl]-ethyl}-amide

Prepared analogously to Compound 1 using IM46 and IM31. Yield=0.696 g(62%). 1H-NMR (500 MHz, DMSO) δ 8.56 (d, 1H), 8.08 (s, 1H), 7.63 (d,1H), 7.27 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.78 (d, 1H), 5.47 (m,1H) 4.92 (m, 1H), 3.91 (m, 1H), 3.84 (m, 1H), 3.73 (m, 2H), 2.20 (m,2H), 1.95 (m, 2H), 1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 353.3 (MH+),t_(R)=1.45 min (method A).

Compound 15: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid((S)-1-[1,3]dioxolo[4, 5-b]pyridin-6-yl-ethyl)-amide

Prepared analogously to Compound 1 using IM46 and IM32. Yield=0.572 g(42%). 1H-NMR (500 MHz, DMSO) δ 8.54 (d, 1H), 7.52 (s, 1H), 7.27 (m,2H), 7.20-7.15 (m, 2H), 7.10 (d, 2H), 6.11 (s, 2H), 4.91 (m, 1H), 2.20(m, 1H), 1.88 (m, 1H), 1.35 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 311.1(MH+), t_(R)=0.61 min (method B).

Compound 16: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and IM33. Yield=0.877 g(39%). 1H-NMR (500 MHz, DMSO) δ 8.52 (d, 1H), 7.68 (s, 1H), 7.27 (m,2H), 7.22 (s, 1H), 7.18 (m, 1H), 7.10 (d, 2H), 4.92 (m, 1H), 4.37 (d,2H), 4.22 (d, 2H), 2.20 (m, 1H), 1.90 (m, 1H), 1.35 (m, 4H), 1.20 (m,1H). LC-MS (m/z) 325.5 (MH+). t_(R)=1.28 min (method A).

Compound 17: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(2-ethoxy-pyrimidin-5-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and IM34. Yield=0.195 g(32%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.52 (s, 2H), 7.26 (m,2H), 7.16 (s, 1H), 7.10 (d, 2H), 4.92 (m, 1H), 4.32 (m, 2H), 2.20 (m,1H), 1.88 (m, 1H), 1.40 (d, 3H), 1.35 (m, 1H), 1.31 (t, 3H), 1.20 (m,1H). LC-MS (m/z) 312.2 (MH+), t_(R)=0.62 min (method B).

Compound 18: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-chloro-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and commercially available(S)-1-(6-Chloro-pyridin-3-yl)-ethylamine (Aurora building blockscatalogue nr A06.814.555). Yield=1.40 g (71%). 1H-NMR (500 MHz, DMSO) δ8.68 (d, 1H), 8.36 (s, 1H), 7.78 (d, 1H), 7.48 (d, 1H), 7.28 (m, 2H),7.18 (m, 1H), 7.11 (d, 2H), 4.99 (m, 1H), 2.20 (m, 1H), 1.92 (m, 1H),1.37 (m, 4H), 1.20 (m, 1H). LC-MS (m/z) 301.2 and 303.1 (MH+),t_(R)=0.67 min (method B).

Compound 19: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(S)-1-[6-(oxetan-3-yloxy)-pyridin-3-yl]-ethyl}-amide

(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-chloro-pyridin-3-yl)-ethyl]-amide (Compound 18) (2.00 g, 6.65mmol) was dissolved in DMF (50 ml). Oxetan-3-ol (4.00 g, 54 mmol) anddicesium carbonate (16.2 g, 49.9 mmol) were added and the mixture washeated at 100° C. ON. The mixture was poured out into brine andextracted with EtOAc. The organic layer was washed with brine, dried(MgSO4) and was filtered and then evaporated to dryness. The residue wastransferred to a silica gel column and eluded with EtOAc/heptanes 1:1 togive Compound 19 as a solid. This solid was dissolved in a mixture ofTHF (10 ml), EtOAc (20 mL) and heptanes (10 ml). The mixture wasconcentrated to approx. 15 mL in vacuo and this solution was cooled inan ice/water bath. A white precipitate formed. The solids was collectedby filtration and dried in vacuo to give the title compound as colorlesscrystals (0.097 g, 4%). %). 1H-NMR (500 MHz, DMSO) δ 8.55 (d, 1H), 8.04(s, 1H), 7.70 (d, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.87(d, 1H), 5.52 (m, 1H), 4.95 (m, 1H), 4.87 (m, 2H), 4.53 (m, 2H), 2.20(m, 1H), 1.90 (m, 1H), 1.37 (m, 4H), 1.21 (m, 1H). LC-MS (m/z) 339.2(MH+), t_(R)=0.63 min (method B). Mp=151-153 C.

Compound 20: (1S,2S)-2-Phenyl-cyclopropane carboxylic acid[(S)-1-(6-cyanomethoxy-pyridin-3-yl)-ethyl]-amide

Compound 20a was prepared analogously to Compound 1 using IM46 and IM35for the first step. Yield of Compound 20a=1.50 g (71%). Pure on TLC(Eluent EtOAc, Rf=0.5). This material (1.50 g, 4.36 mmol) was dissolvedin a mixture of DMSO (50 ml) and THF (50 ml) and1-Hydroxy-1,2-benziodoxol-3(1H)-one 1-Oxide (1.34 g, 4.8 mmol) was addedand the mixture was stirred at rt overnight. The mixture was added to amixture of brine and EtOAc and the phases were separated. The organicphases was dried over MgSO4 and was rotovaped. The crude product waspurified by silica gel chromatography (Eluent EtOAc). Yield of Compound20b=1.08 g (72%). Pure on TLC (Eluent EtOAc, Rf=0.7). This material(1.05 g, 3.24 mmol) was dissolved in THF (10 ml), and MeCN (50 ml) andadded drop wise to a solution of 1-Hydroxy-1,2-benziodoxol-3(1H)-one1-Oxide (1.36 g, 4.86 mmol) in ammonia in water (13 M, 25 ml) and THF (5ml) and MeCN (5 ml). The mixture was stirred at rt ON. The organicphases was dried over MgSO4 and was rotovaped. The crude product waspurified by silica gel chromatography (Eluent EtOAc in heptanes 4:1) togive 177 mg impure product. This material was THF (10 ml) and EtOAc (10ml) and heptanes (10 ml) were added. The mixture was rotovaped untilaprox 10 ml solvent was left and then cooled in an ice bath. A solidprecipitated and was collected and dried in vac. Yield of Compound20=0.054 g (5%). Pure on LCMS and H-NMR. Mp=163-165 C. LC-MS (m/z) 322.1(MH+), t_(R)=1.03 min (method A). 1H-NMR (500 MHz, DMSO) δ 8.60 (d, 1H),8.17 (s, 1H), 7.75 (d, 1H), 7.27 (m, 2H), 7.17 (m, 1H), 7.11 (d, 2H),6.95 (d, 1H), 5.19 (s, 2H), 4.97 (m, 1H), 2.21 (m, 1H), 1.92 (m, 1H),1.38 (m, 4H), 1.21 (m, 1H).

Compound 21: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide

Triethylamine (0.384 mL, 2.75 mmol) was added to a mixture oftrans-2-phenyl-1-cyclopropanecarboxylic acid IM46 (223 mg, 1.38 mmol)and O-(benzotriazol-1-yl)-N,N, N′,N′-tetramethyluroniumhexafluorophosphate (522 mg, 1.38 mmol) suspended in DMF (2 mL) in asmall vial. The vial was vigorously agitated for 30 seconds and thenleft for 5 minutes. This mixture was added drop wise to(R)-2-Amino-2-(6-propoxy-pyridin-3-yl)-ethanol IM36 (270 mg, 1.4 mmol)dissolved in DMF (3 mL). After 1 h the mixture was poured into a mixtureof EtOAc (40 mL) and brine (20 mL). The organic layer was dried overMgSO₄ and evaporated to dryness. Flash chromatography (silica, 10-100%EtOAc in heptanes) gave the title compound as a white solid (0.134 g,29%). LC-MS (m/z) 341.0 (MH+), t_(R)=1.52 min (method A). 1H-NMR (600MHz, DMSO) δ 8.53 (d, J=8.2 Hz, 1H), 8.04 (br s, 1H), 7.64-7.57 (m, 1H),7.30-7.23 (m, 2H), 7.19-7.14 (m, 1H), 7.10 (d, J=7.3 Hz, 2H), 6.74 (d,J=8.5 Hz, 1H), 4.96-4.90 (m, 1H), 4.88-4.80 (m, 1H), 4.16 (t, J=6.7 Hz,2H), 3.61-3.49 (m, 2H), 2.23-2.15 (m, 1H), 2.04-1.95 (m, 1H), 1.74-1.64(m, 2H), 1.40-1.32 (m, 1H), 1.23-1.13 (m, 1H), 0.94 (t, J=7.4 Hz, 3H).

Compound 22: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.39 g,2.03 mmol) and 1-hydroxybenzotriazole (0.366 g, 2.71 mmol) were added toa stirred mixture of IM46 (0.22 g, 1.36 mmol) and commercially available(R)-2-amino-2-(6-trifluoromethyl-pyridin-3-yl)-ethanol hydrochloride(Supplier Netchem Inc., Catalog No 517882) (0.494 g, 2.03 mmol) andN,N-diisopropylethylamine (0,472 ml, 2.71 mmol) in THF (20 ml). Thesolution was stirred at rt overnight. Water was added and the mixturewas extracted with EtOAc (3×80 ml). The combined organic phases werewashed with brine, dried over MgSO4, filtered and the solvent wasevaporated of in vac. The crude product was purified by silica gelchromatography (EtOAc in heptanes 10:1). Yield of Compound 22 475 mg(78%). 1H-NMR (500 MHz, DMSO) δ 8.77 (d, 1H), 8.74 (s, 1H), 8.00 (d,1H), 7.88 (d, 1H), 7.27 (m, 2H), 7.18 (m, 1H), 7.13 (d, 2H), 5.04 (m,2H), 3.64 (m, 2H), 2.22 (m, 1H), 2.07 (m, 1H), 1.37 (m, 1H), 1.37 (m,1H), 1.23 (m, 1H). LC-MS (m/z) 351.1 (MH+), t_(R)=1.51 min (method A).

Compound 23: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(5-cyano-pyridin-2-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 22 using IM46 and commerciallyavailable 6-((R)-1-amino-2-hydroxy-ethyl)-nicotinonitrile (SupplierNetchem Inc., Catalog No 549885). Yield of Compound 23 230 mg (61%).1H-NMR (500 MHz, DMSO) δ 8.97 (s, 1H), 8.72 (d, 1H), 8.26 (d, 1H), 7.52(d, 1H), 7.27 (m, 2H), 7.18 (t, 1H), 7.11 (d, 2H), 5.05-4.95 (m, 2H),3.70 (m, 2H), 2.20 (m, 1H), 2.17 (m, 1H), 1.36 (m, 1H), 1.20 (m, 1H).LC-MS (m/z) 308.1 (MH+), t_(R)=0.1.21 min (method A).

Compound 24: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(6-methoxy-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 22 using IM46 and commerciallyavailable (R)-2-Amino-2-(6-methoxy-pyridin-3-yl)-ethanol (SupplierNetchem Inc., Catalog No 517926). Yield of Compound 24=763 mg (22%).1H-NMR (500 MHz, DMSO) δ 8.53 (d, 1H), 8.09 (s, 1H), 7.63 (d, 1H), 7.27(m, 2H), 7.15 (m, 1H), 7.12 (m, 2H), 6.77 (d, 1H), 4.95 (m, 2H), 4.85(m, 2H), 3.83 (s, 3H), 3.57 (m, 2H), 2.21 (m, 1H), 2.00 (m, 1H), 1.37(m, 1H), 1.19 (m, 1H). LC-MS (m/z) 313.1 (MH+), t_(R)=1.53 min (methodA).

Compound 25: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(6-methyl-pyridin-3-yl)-ethyl]-amide

N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.316 g,1.65 mmol) and 1-hydroxybenzotriazole (0.223 g, 1.65 mmol) were added toa stirred mixture of IM46 (0.18 g, 1.1 mmol) and commercially available(R)-2-Amino-2-(6-methyl-pyridin-3-yl)-ethanol dihydrochloride (SupplierNetchem Inc., Catalog No 549945) (0.128 g, 1.21 mmol) andN,N-diisopropylethylamine (0.575 ml, 3.30 mmol) in THF (10 ml). Thesolution was stirred at rt overnight. Water was added and the mixturewas extracted with EtOAc. The organic phase was rotovaped to produce 140mg of Compound 25a. LC-MS (m/z) 441.4 (MH+), t_(R)=1.44 min (method A).Compound 25a was dissolved in THF and LiOH (IM) was added and themixture was stirred 30 min. A solid precipitated and was isolated byfiltration and dried in vac. Yield of Compound 25=110 mg (34%). 1H-NMR(500 MHz, DMSO) δ 8.53 (d, 1H), 8.09 (s, 1H), 7.63 (d, 1H), 7.27 (m,2H), 7.15 (m, 1H), 7.12 (m, 2H), 6.77 (d, 1H), 4.95 (m, 2H), 4.85 (m,2H), 3.83 (s, 3H), 3.57 (m, 2H), 2.21 (m, 1H), 2.00 (m, 1H), 1.37 (m,1H), 1.19 (m, 1H). LC-MS (m/z) 297.3 (MH+). t_(R)=0.78 min (method A).

Compound 26: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 21 using IM46 and IM37. Yield ofCompound 26=667 mg (77%). 1H-NMR (600 MHz, DMSO) δ 8.52 (d, 1H), 8.03(s, 1H), 7.60 (d, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.67(d, 1H), 5.20 (m, 1H), 4.92 (t, 1H), 4.83 (m, 1H), 3.55 (m, 2H), 2.20(m, 1H), 2.00 (m, 1H), 1.35 (m, 1H), 1.24 (d, 6H), 1.19 (m, 1H). LC-MS(m/z) 341.0 (MH+), t_(R)=1.45 min (method A).

Compound 27: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM47 and IM38. Yield ofCompound 27=90 mg (19%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.05 (s,1H), 7.62 (m, 1H), 7.28 (m, 1H), 6.97 (m, 3H), 6.73 (d, 1H), 4.83 (m,1H), 4.24 (m, 2H), 3.55 (m, 2H), 2.22 (m, 1H), 2.03 (m, 1H), 1.37 (m,1H), 1.28 (t, 3H), 1.22 (m, 1H). LC-MS (m/z) 345.0 (MH+), t_(R)=0.63 min(method B).

Compound 28: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM48 and IM38. Yield ofCompound 28=93 mg white solid. (54%). 1H-NMR (600 MHz, DMSO) δ 8.56 (d,1H), 8.07 (s, 1H), 7.62 (m, 1H), 7.18 (m, 2H), 7.12 (m, 2H), 6.77 (d,1H), 4.93 (t, 1H), 4.83 (m, 1H), 4.25 (dd, 2H), 3.52 (m, 2H), 2.27 (m,1H), 1.97 (m, 1H), 1.30 (m, 4H), 1.15 (m, 1H). LC-MS (m/z) 345.0 (MH+),LC-MS (m/z) 345.0 (MH+), t_(R)=1.36 min (method A).

Compound 29: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(6-propoxy-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 21 using IM47 and IM36. Yield=150 mg(30%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.03 (s, 1H), 7.62 (d,1H), 7.29 (m, 1H), 6.95 (m, 3H), 6.74 (d, 1H), 4.93 (m, 1H), 4.84 (m,1H), 4.16 (t, 2H), 3.55 (m, 2H), 2.23 (m, 1H), 2.03 (m, 1H), 1.68 (m,2H), 1.37 (m, 1H), 1.25 (m, 1H), 0.93 (t, 3H). LC-MS (m/z) 359.1 (MH+),t_(R)=1.57 min (method A).

Compound 30: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-2-hydroxy-1-(5-propoxy-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 21 using IM48 and IM36. Yield 176 mg(36%). 1H-NMR (600 MHz, DMSO) δ 8.52 (d, 1H), 8.05 (s, 1H), 7.63 (d,1H), 7.14 (m, 2H), 7.09 (m, 2H), 6.74 (d, 1H), 4.92 (t, 1H), 4.85 (m,1H), 4.15 (t, 2H), 3.55 (m, 2H), 2.22 (m, 1H), 1.97 (m, 1H), 1.70 (m,2H), 1.34 (m, 1H), 1.18 (m, 1H), 0.92 (t, 3H).

Compound 31: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM46 and IM40. Yield=785 mg(66%). 1H-NMR (600 MHz, CDCl₃) δ 8.62 (s, 1H), 7.52 (d, 1H), 7.26 (m,2H), 7.20 (m, 1H), 7.08 (d, 2H), 6.71 (d, 1H), 6.27 (m, 1H), 5.05 (m,1H), 4.31 (s, 2H), 3.91 (m, 2H), 2.51 (m, 2H), 1.67 (m, 2H), 1.31 (m,1H). LC-MS (m/z) 330.3 (MH+), t_(R)=1.32 min (method A).

Compound 32: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM47 and IM41. Yield=104 mg(44%). 1H-NMR (600 MHz, DMSO) δ 8.52 (d, 1H), 8.03 (s, 1H), 7.61 (m,1H), 7.29 (m, 1H), 6.97 (m, 3H), 6.72 (d, 1H), 4.93 (m, 1H), 4.85 (m,1H), 3.55 (m, 2H), 2.22 (m, 1H), 2.02 (m, 1H), 1.37 (m, 1H), 1.25 (m,4H). LC-MS (m/z) 347.2 (MH+), t_(R)=0.64 min (method A).

Compound 33: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 22 using IM46 and IM38. Yield=90 mg(28%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.06 (s, 1H), 7.52 (m,1H), 7.26 (m, 2H), 7.16 (m, 1H), 7.10 (d, 2H), 6.73 (d, 1H), 4.95 (t,1H), 4.87 (m, 1H), 4.25 (m, 2H), 3.55 (m, 2H), 2.20 (m, 1H), 2.02 (m,1H), 1.36 (m, 1H), 1.28 (t, 3H), 1.20 (m, 1H). LC-MS (m/z) 327.4 (MH+),t_(R)=0.57 min (method B).

Compound 34: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-(1,1,2,2,2-d₅)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM48 and IM39. Yield=130 mg(41%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.06 (s, 1H), 7.62 (m,1H), 7.14 (m, 2H), 7.10 (m, 2H), 6.73 (d, 1H), 4.95 (br s, 1H), 4.84 (m,1H), 3.55 (m, 2H), 2.22 (m, 1H), 1.96 (m, 1H), 1.34 (m, 1H), 1.18 (m,1H). LC-MS (m/z) 350.2 (MH+), t_(R)=1.41 min (method A).

Compound 35: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM48 and IM40. Yield=144 mg(41%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.08 (s, 1H), 7.63 (m,1H), 7.13 (m, 2H), 7.10 (m, 2H), 6.73 (d, 1H), 4.97 (br s, 1H), 4.86 (m,1H), 4.24 (s, 2H), 3.57 (m, 2H), 2.23 (m, 1H), 1.97 (m, 1H), 1.37 (m,1H), 1.20 (m, 1H). LC-MS (m/z) 347.9 (MH+), t_(R)=1.39 min (method A).

Compound 36: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM46 and IM41. Yield=148 mg(67%). 1H-NMR (600 MHz, DMSO) δ 8352 (d, 1H), 8.05 (s, 1H), 7.61 (d,1H), 7.50 (m, 2H), 7.15 (m, 1H), 7.10 (d, 2H), 6.72 (d, 1H), 4.94 (t,1H), 4.85 (m, 1H), 3.55 (m, 2H), 2.18 (m, 1H), 1.97 (m, 1H), 1.35 (m,1H), 1.27 (s, 3H), 1.20 (m, 1H). LC-MS (m/z) 329.2 (MH+), t_(R)=0.61 min(method B).

Compound 37: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-(1,1-d₂)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM48 and IM41. Yield=123 mg(52%). 1H-NMR (600 MHz, DMSO) δ 8.52 (d, 1H), 8.06 (s, 1H), 7.62 (m,1H), 7.14 (m, 2H), 7.10 (m, 2H), 6.73 (d, 1H), 4.92 (t, 1H), 4.84 (m,1H), 3.55 (m, 2H), 2.22 (m, 1H), 1.96 (m, 1H), 1.34 (m, 1H), 1.28 (s,3H), 1.18 (m, 1H). LC-MS (m/z) 347.2 (MH+), t_(R)=1.41 min (method 8).

Compound 38: (1S,2S)-2-Phenyl-cyclopropane carboxylic acid[(R)-1-(6-(1,1,2,2-d₅)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM46 and IM39. Yield=98 mg(32%). 1H-NMR (600 MHz, DMSO) δ 8.52 (d, 1H), 8.05 (s, 1H), 7.61 (d,1H), 7.26 (t, 2H), 7.16 (t, 1H), 7.10 (d, 2H), 6.72 (d, 1H), 4.93 (t,1H), 4.83 (m, 1H), 3.55 (m, 2H), 2.18 (m, 1H), 1.99 (m, 1H), 1.35 (m,1H), 1.20 (m, 1H). LC-MS (m/z) 332.2 (MH+), t_(R)=0.61 min (method B).

Compound 39: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-(2,2,2-d₃)-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM47 and IM40. Yield=101 mg(29%). 1H-NMR (600 MHz, DMSO) δ 8.53 (d, 1H), 8.05 (s, 1H), 7.61 (d,1H), 7.28 (m, 1H), 7.0-6.95 (m, 3H), 6.72 (d, 1H), 4.93 (t, 1H), 4.83(m, 1H), 4.22 (s, 2H), 3.55 (m, 2H), 2.23 (m, 1H), 2.02 (m, 1H), 1.37(m, 1H), 1.27 (m, 1H). LC-MS (m/z) 348.0 (MH+), t_(R)=1.43 min (methodA).

Compound 40: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM46 and IM44. Yield=53 mg(30%). 1H-NMR (600 MHz, DMSO) δ 8.50 (d, 1H), 8.03 (s, 1H), 7.61 (d,1H), 7.25 (m, 2H) 7.16 (m, 1H), 7.10 (m, 2H), 6.71 (d, 1H), 5.09 (m,1H), 4.90 (t, 1H), 4.82 (m, 1H), 3.55 (m, 2H), 2.37 (m, 2H), 2.21 (m,11H), 2.00 (m, 4H), 1.76 (m, 1H), 1.61 (m, 1H), 1.32 (m, 1H), 1.20 (m,1H). LC-MS (m/z) 353.1 (MH+), t_(R)=0.70 min (method B).

Compound 41: (1S,2S)-2-(3-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM47 and IM44. Yield=38 mg(20%). 1H-NMR (600 MHz, DMSO) δ 8.50 (d, 1H), 8.03 (s, 1H), 7.61 (d,1H), 7.27 (m, 1H), 6.95 (m, 3H), 6.71 (d, 1H), 5.08 (m, 1H), 4.95 (br.s, 1H), 4.82 (m, 1H), 3.55 (m, 2H), 2.37 (m, 2H), 2.22 (m, 1H), 2.02 (m,4H), 1.75 (m, 1H), 1.61 (m, 1H), 1.37 (m, 1H), 1.27 (m, 1H). LC-MS (m/z)371.1 (MH+), t_(R)=0.71 min (method B).

Compound 42: (1S,2S)-2-(4-Fluoro-phenyl)-cyclopropanecarboxylic acid[(R)-1-(6-cyclobutoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM48 and IM44. Yield=84 mg(45%). 1H-NMR (600 MHz, DMSO) δ 8.50 (d, 1H), 8.03 (s, 1H), 7.61 (d,1H), 7.14 (m, 2H), 7.09 (m, 2H), 6.71 (d, 1H), 5.08 (m, 1H), 4.92 (t,1H), 4.82 (m, 1H), 3.55 (m, 2H), 2.37 (m, 2H), 2.21 (m, 1H), 2.05-1.95(m, 4H), 1.75 (m, 1H), 1.61 (m, 1H), 1.32 (m, 1H), 1.17 (m, 1H). LC-MS(m/z) 371.1 (MH+), t_(R)=0.71 min (method B).

Compound 43: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid((R)-2-hydroxy-1-{6-[(R)-(tetrahydro-furan-3-yl)oxy]-pyridin-3-yl}-ethyl)-amide

Prepared analogously to Compound 21 using IM46 and IM43. Yield=1.34 gwhite solid (60%). ¹H NMR (400 MHz, CDCl₃): δ 8.08 (s, 1H), 7.51 (d,J=8.4 Hz, 1H), 7.18-7.25 (m, 3H), 7.04-7.06 (m, 2H), 6.68-6.71 (m, 1H),6.36-6.39 (m, 1H), 5.50-5.53 (m, 1H), 5.04-5.05 (m, 1H), 3.88-4.01 (m,6H), 2.48-2.50 (m, 1H), 2.21-2.26 (m, 1H), 2.11-2.13 (m, 1H), 1.62-1.71(m, 2H), 1.27-1.31 (m, 1H). LC-MS (m/z) 369.2 (MH+), t_(R)=2.04 min(method WXE-AB01). [α]_(D) ²⁰=178.6 (C=0.2, CHCl₃)

Compound 44:(1S,2S)—N-[(1R)-2-hydroxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide

Prepared analogously to Compound 21 using IM46 and IM42. Yield=2.10 gwhite solid (50%). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (m, 1H), 7.52-7.55(m, 1H), 7.29 (m, 1H), 7.25-7.27 (m, 1H), 7.20-7.21 (m, 1H), 7.17-7.19(d, J=7.2 Hz, 2H), 6.70-6.73 (d, J=8.8 Hz, 1H), 6.34-6.36 (d, J=7.2 Hz,1H), 5.50-5.53 (m, 1H), 5.04-5.05 (d, J=6.8 Hz, 1H), 3.94-4.03 (m, 2H),3.85-3.91 (m, 4H), 2.48-2.50 (m, 1H), 2.21-2.26 (m, 1H), 2.11-2.13 (m,1H), 1.62-1.71 (m, 2H), 1.27-1.31 (m, 1H). LC-MS (m/z) 369.2 (MH+),t_(R)=2.03 min (method WXE-AB01). [α]_(D) ²⁰=160.9 (C=0.21, CHCl₃).

Compound 45:(1S,2S)-2-((Z)-1-Methylene-penta-2,4-dienyl)-cyclopropanecarboxylic acid{(R)-2-hydroxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide

Prepared analogously to Compound 1 using IM46 and IM45. Yield=2.5 gwhite solid (44%). ¹H NMR ((400 MHz, CDCl₃): δ8.09 (s, 1H), 7.52-7.55(m, 1H), 7.27-7.28 (m, 1H), 7.25-7.26 (m, 1H), 7.20 (m, 1H), 7.06-7.08(t, J=4.2 Hz, 2H), 6.70-6.72 (d, J=6.4 Hz, 1H), 6.34-6.36 (d, J=7.2 Hz,1H), 5.18-5.21 (m, 1H), 5.04-5.05 (d, J=6.8 Hz, 1H), 3.62-3.99 (m, 4H),3.56-3.62 (m, 2H), 2.46-2.50 (m, 1H), 2.01-2.06 (m, 2H), 1.74-1.80 (m,2H), 1.62-1.70 (m, 2H), 1.27-1.30 (m, 1H). [α]_(D) ²⁰=144.3 (c=0.204g/100 mL, CHCl₃).

Compound 46: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide

NaH (60% suspension in mineral oil) (2.06 g, 51.5 mmol) was suspended inDMF and the reaction vessel was cooled in an ice bath.(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide (Compound 33) (15g, 46 mmol) was dissolved in DMF (50 ml) and added drop wise to thesodium hydride suspension at 5-8 C over 20 minutes. The solution wasstirred 30 minutes. Methyl iodide (3.30 ml, 53.0 mmol) dissolved in DMF(25 ml) was added drop wise at 5-12 C over 10 minutes and the mixturewas stirred at 7-8 C for 30 minutes. The mixture was added to a brinesolution and extracted with EtOAc. The organic layer was washed withmore brine, dried (MgSO4) filtered and the solvent was evaporated off.The crude product was purified by silica gel chromatography (eluentEtOAc in heptanes 4:1). The fractions that contained the product wascollected and the solvent was removed in vac. The residue wasredissolved in THF (50 ml) EtOAc (100 ml) and heptanes (25 ml). Themixture was concentrated until 40 ml remained and cooled in ice. A whitesolid precipitated and was collected by filtration. Yield: 6.75 g (43%)of Compound 46. LC-MS (m/z) 341.2 (MH+), t_(R)=0.64 min (method B).

1H-NMR (500 MHz, DMSO) δ 8.62 (d, 1H), 8.08 (br s, 1H), 7.63 (d, 1H),7.27 (m, 2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.74 (d, 1H), 5.05 (m, 1H),4.26 (m, 2H), 3.55-3.46 (m, 2H), 3.26 (s, 3H), 2.20 (m, 1H), 1.99 (m,1H), 1.38 (m, 1H), 1.29 (t, 3H), 1.20 (m, 1H).

Compound 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]-ethyl]-2-phenyl-cyclopropanecarboxamide

Prepared analogously to Compound 46 using Compound 43 (0.90 g).

Yield=490 mg (53%) as a solid. ¹H NMR (400 MHz, CDCl₃): δ8.12 (d, J=2.4Hz, 1H), 7.54-7.57 (m, 1H), 7.25-7.28 (m, 2H), 7.18-7.21 (m, 1H),7.05-7.07 (m, 2H), 6.68-6.70 (d, J=8.8 Hz, 1H), 6.37-6.39 (d, J=8.0 Hz,1H), 5.51-5.54 (m, 1H), 5.10-5.12 (m, 1H), 3.87-4.04 (m, 4H), 3.66-3.69(m, 1H), 3.60-3.63 (m, 1H), 3.38 (s, 3H), 2.45-2.46 (m, 1H), 2.21-2.26(m, 1H), 1.60-1.68 (m, 2H), 1.25-1.28 (m, 1H). LC-MS: t_(R)=0.53 min(method B), m/z=383.2 [M+H]⁺. [α]_(D) ²⁰=188.2 (C=0.176, CHCl₃).

Compound 48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide

Prepared analogously to Compound 46 using Compound 44 (841 mg).

Yield=645 mg (44%) as a solid. ¹H NMR (400 MHz, CDCl₃): δ8.10-8.11 (d,J=2.4 Hz, 1H), 7.54-7.57 (m, 1H), 7.25-7.28 (m, 2H), 7.18-7.21 (m, 1H),7.05-7.07 (m, 2H), 6.68-6.70 (d, J=8.8 Hz, 1H), 6.37-6.39 (d, J=8.0 Hz,1H), 5.51-5.54 (m, 1H), 5.10-5.12 (m, 1H), 3.87-4.04 (m, 4H), 3.66-3.69(m, 1H), 3.60-3.63 (m, 1H), 3.38 (s, 3H), 2.45-2.46 (m, 1H), 2.21-2.26(m, 1H), 1.60-1.68 (m, 2H), 1.25-1.28 (m, 1H). LC-MS: t_(R)=0.62 min(method B), m/z=383.2 [M+H]⁺. [α]_(D) ²⁰=162.5 (C=0.225, CHCl₃).

Compound 49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide

Prepared analogously to Compound 46 using Compound 45. Yield=343 mg(20%) as a solid. ¹H NMR (400 MHz, CDCl₃): δ8:10-8.11 (d, J=2.4 Hz, 1H),7.54-7.57 (m, 1H), 7.25-7.29 (m, 2H), 7.18-7.21 (m, 1H), 7.05-7.07 (m,2H), 6.66-6.68 (t, J=4.2 Hz, 1H), 6.38-6.40 (d, J=7.2 Hz, 1H), 5.20-5.21(m, 1H), 5.10-5.12 (m, 1H), 3.94-3.99 (m, 2H), 3.57-3.69 (m, 4H), 3.37(s, 3H), 2.42-2.49 (m, 1H), 2.02-2.08 (m, 2H), 1.61-1.79 (m, 4H),1.25-1.28 (m, 1H) α]_(D) ²⁰=159.3 (c=0.198 g/100 mL, CHCl₃). LC-MS (m/z)383.15 (MH+), t_(R)=0.54 min (method B).

Compound 50: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid {(S)-1-[6(oxetan-3-yloxy)-pyridin-3-yl]-ethyl}-amide

(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-chloro-pyridin-3-yl)-ethyl]-amide (Compound 18) (2.00 g, 6.65mmol) was dissolved in DMF (40 ml).N,N-dimethylhydroxylaminehydrochloride (5.00 g, 51.2 mmol) and dicesiumcarbonate (25 g, 76.7 mmol) were added and the mixture was heated at 95C 3 days. The mixture was poured out into brine and extracted withEtOAc. The organic layer was washed with brine, dried (MgSO4) and wasfiltered and then evaporated to dryness. The residue was transferred toa silica gel column and eluded with EtOAc to give Compound 50 as asolid. This solid was dissolved in a mixture of THF (10 ml), EtOAc (10ml) and heptanes (10 ml). The mixture was concentrated to approx. 10 mlvolume and this solution was cooled in an ice/water bath. A whiteprecipitate formed. The solids was collected by filtration and dried invacuo to give the title compound as a white solid (0.044 g, 2%). 1H-NMR(500 MHz, DMSO) δ 8.43 (d, 1H), 8.02 (s, 1H), 7.45 (d, 1H), 7.25 (m,2H), 7.17 (m, 1H), 7.10 (d, 2H), 6.61 (d, 1H), 4.83 (m, 1H), 3.98 (m,6H), 2.19 (m, 1H), 1.90 (m, 1H), 1.35 (m, 4H), 1.21 (m, 1H). LC-MS (m/z)310.2 (MH+), t_(R)=0.46 min (method B). Mp=171-181 C.

Compound 51: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(S)-1-(6-ethanesulfonyl-pyridin-3-yl)-ethyl]-amide

Prepared analogously to Compound 1 using IM46 and(S)-1-(6-Methanesulfonyl-pyridin-3-yl)-ethylamine (prepared from1-(6-Methanesulfonyl-pyridine-3-yl)-ethanone analogously to IM24, whichwas prepared from commercially available5-Bromo-2-methanesulfonyl-pyridine CAS 98626-95-0). Yield from IM46=1.54g (68%). 1H-NMR (500 MHz, DMSO) δ 8.80 (d, 1H), 8.72 (s, 1H), 8.02 (m,2H), 7.27 (m, 2H), 7.20 (s, 1H), 7.12 (d, 2H), 5.08 (m, 1H), 3.27 (s,3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.42 (d, 3H), 1.37 (m, 1H), 1.22 (m,1H). LC-MS (m/z) 345.1 (MH+), t_(R)=1.21 min (method A).

Compound 52: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(5-ethoxy-pyridin-2-yl)-2-hydroxy-ethyl]-amide

Prepared analogously to Compound 21 using IM46 and(R)-2-Amino-2-(5-ethoxy-pyridin-2-yl)-ethanol (prepared fromcommercially available 2-Bromo-5-ethoxy-pyridine CAS 42834-01-5analogously to IM36). Compound 52 was further purified by SFC (Column:Chiralpack OJ250×30 mm, Mobile phase: Supercrital CO₂/MeOH+NH₄OH=55/45at 50 mL/min, column temperature: 38° C., Nozzle Pressure: 100 Bar,Nozzle Temp=60° C., Evaporator temp=20 C, Trimmer temp=25° C., Detector:220 nm). Yield=163 mg. 1H NMR (CDCl3 400M Hz, TMS): δ 8.15 (d, J=2.8 Hz,1H), 7.08-7.31 (m, 6H), 7.06 (d, J=7.2 Hz, 2H), 5.11-5.15 (m, 1H),4.00-4.08 (m, 3H), 3.87-3.90 (m, 1H), 2.47-2.52 (m, 1H), 1.63-1.76 (m,3H), 1.43 (t, J=7.2 Hz, 3H), 1.27-1.31 (m, 1H); [α]20,D=182.0 (c=0.234g/100 mL, EtOH)

In Vitro Assays

The nicotinic acetylcholine receptor α7 is a calcium-permeable ionchannel, whose activity can be measured by over expression in mammaliancells or oocytes. These two individual assays are described in Example 2and 3, respectively.

Example 2: α7 NNR Flux Assay

The nicotinic acetylcholine receptor α7 is a calcium-permeable ionchannel, whose activity can be measured by over expression in mammaliancells or oocytes in this version of the assay, the human α7 receptor isstably expressed in the rat GH4C1 cell line. The assay was used toidentify positive allosteric modulators (PAMs) of the α7 receptor.Activation of the channel was measured by loading cells with thecalcium-sensitive fluorescent dye Calcium-4 (Assay kit from MolecularDevices), and then measuring real-time changes in fluorescence upontreatment with test compounds.

The cell line ChanClone GH4C1-nAChRalpha7 from Genionics was seeded fromfrozen stock in 384-well plates in culture media 2-3 days beforeexperiment to form an approximately 80% confluent layer on the day ofexperiment.

Cell Plating and Dye Loading

The cell culture were split into “22.5 cm×22.5 cm”-plates withapproximately 100×10³ cells/cm². After four days incubation in ahumidified incubator at 37° C. and 5% CO₂, it had grown to an 80-90%confluent layer, and the cells were harvested.

Culture Media:

500 mL DMEM/F12 (Gibco 31331)

50 mL FBS (Gibco 10091-155, lot 453269FD)

5 mL Sodium Pyruvate (Gibco 11360)

5 mL Pen/Strep (Gibco 15140)

0.1 mg/mL G-418 (Gibco 11811-064)

Two or three days before the experiment the cells were seeded in 384well plates from Greiner bio-one (781946, CELLCOAT, Poly-D-Lysine,black, μClear).

The media was poured off and the plate washed with PBS and left todrain. 5 mL Trypsin was added, cells were washed and incubated (at roomtemperature) for about 10 seconds. Trypsin was poured of quickly and thecells were incubated for 2 minutes at 37° C. (if the cells were notalready detached). Cells were resuspended in 10 mL culture media andtransferred to 50 mL tubes.

The cell suspension was counted (NucleoCounter, total cell count) fromthe first plates to estimate the total cell number of the whole batch.

The cells were seeded in 384 well plates with 30 μL/well (30000cells/well) while stirring the cell suspension or otherwise preventingthe cells from precipitating.

The plates were incubated at room temperature for 30-45 minutes.

The plates were placed in incubator for two days (37° C. and 5% CO₂).

Loading the Cells

The loading buffer was 5% v/v Calcium-4 Kit and 2.5 mM Probenecid inassay buffer.

190 mL assay buffer

10 mL Kit-solution

2 mL 250 mM Probenecid

This volume was enough for 3×8 cell plates.

Culture media were removed from the cell plates and 20 μL loading bufferwas added in each well. The cell plates were placed in trays andincubated 90 minutes in the incubator (37° C.). Thereafter the plateswere incubated 30 minutes at room temperature, still protected fromlight.

Now the cell plates were ready to run in the Functional Drug ScreeningSystem (FDSS).

The assay buffer was HBSS with 20 mM HEPES, pH 7.4 and 3 mM CaCl₂.

FDSS Ca Assay

200 nL 10 mM compound solution in DMSO was diluted in 50 μL assaybuffer. The final test concentrations in the cell plates were20-10-5-2.5-1:25-0.625-0.312-0.156-0.078-0.039 μM. Assay buffer and 3 μMPNU-120596 were used for control.

The agonist acetylcholine was added to a final concentration of 20 μM(˜EC100).

In the FDSS7000 the Ex480-Em540 was measured with 1 second intervals.The baseline was made of 5 frames before addition of test compounds, and95 frames more were made before addition of acetylcholine. Themeasurement stopped 30 frames after the 2^(nd) addition. Raw data foreach well were collected as “the maximum fluorescence count” in theinterval 100-131 seconds and as “the average fluorescence count” in theinterval 96-100 seconds. The positive allosteric modulation in the2^(nd) addition was the enhancement of agonist response with testcompound compared to agonist alone.

Results were calculated as % modulation of test compound compared to thereference PNU-120596 set to 100%. From these data EC₅₀ curves weregenerated giving EC₅₀, hill and maximum stimulation.

The compounds of the invention were shown to be PAMs of the α7 receptor.The compounds of the present invention characterized in the flux assaygenerally possess EC₅₀ values below 20.000 nM or less such as below10.000 nM. Many compounds, in fact have EC₅₀ values below 5.000 nM.Table 1 shows EC₅₀ values for exemplified compounds of the invention.

TABLE 1 Compound EC₅₀ (nM) 1 670 2 5600 3 5800 4 8100 5 7700 6 5200 7960 8 3700 9 6200 10 1900 11 3800 12 1200 13 1600 14 1600 15 5600 166800 17 3700 18 3700 19 2400 20 2000 21 640 22 5500 23 7600 24 5200 257300 26 390 27 390 28 620 29 860 30 560 31 1700 32 530 33 1000 34 700 35710 36 1600 37 700 38 970 39 720 40 890 41 1600 42 790 43 2900 44 460046 2900 46 460 47 1000 48 1700 49 1200 50 3200 51 7200 52 2000

Example 3: α7NNR Oocyte Assay

Expression of α7 nACh Receptors in Xenopus oocytes.

Oocytes were surgically removed from mature female Xenepus laevisanaesthetized in 0.4% MS-222 for 10-15 min. The oocytes were thendigested at room temperature for 2-3 hours with 0.5 mg/mL collagenase(type IA Sigma-Aldrich) in OR2 buffer (82.5 mM NaCl, 2.0 mM KCl, 1.0 mMMgCl₂ and 5.0 mM HEPES, pH 7.6). Oocytes avoid of the follicle layerwere selected and incubated for 24 hours in Modified Barth's Salinebuffer (88 mM NaCl, 1 mM KCl, 15 mM HEPES, 2.4 mM NaHCO₃, 0.41 mM CaCl₂,0.82 mM MgSO₄, 0.3 mM Ca(NO₃)₂) supplemented with 2 mM sodium pyruvate,0.1 U/I penicillin and 0.1 μg/I streptomycin. Stage IV oocytes wereidentified and injected with 4.2-48 nl of nuclease free water containing0.1-1.2 ng of cRNA coding for human α7 nACh receptors or 3.0-32 ng ofcRNA coding for rat α7 nACh receptors and incubated at 18° C. for 1-10days when they were used for electrophysiological recordings.

Electrophysiological Recordings of α7 nACh Receptors Expressed inOocytes.

Oocytes were used for electrophysiological recordings 1-10 days afterinjection. Oocytes were placed in a 1 mL bath and perfused with Ringerbuffer (115 mM NaCl, 2.5 mM KCl, 10 mM HEPES, 1.8 mM CaCl₂, 0.1 mMMgCl₂, pH 7.5). Cells were impaled with agar plugged 0.2-1 MO electrodescontaining 3 M KCl and voltage clamped at −90 mV by a GeneClamp 500Bamplifier. The experiments were performed at room temperature. Oocyteswere continuously perfused with Ringer buffer and the drugs were appliedin the perfusate. ACh (30 μM) applied for 30 sec were used as thestandard agonist for activation of the α7 nACh receptors. In thestandard screening set-up the new test compound (10 μM or 30 μM) wereapplied for 1 min of pre-application allowing for evaluation ofagonistic activity followed by 30 sec of co-application with ACh (30 μM)allowing for evaluation of PAM activity. The response of co-applicationwas compared to the agonistic response obtained with ACh alone. The druginduced effects on both the peak response and the total charge (AUC)response were calculated thus giving the effect of drug induced PAMactivity as fold modulation of the control response.

For more elaborate studies doses-response curves can be performed forevaluation of max-fold modulation and EC₅₀ values for both peak and AUCresponses.

1. A method for the treatment of schizophrenia, said method comprisingadministering a therapeutically effective amount of a compound accordingto formula [I] to a patient in need thereof,

wherein: R1, R2, R3, R4 and R5 are H; R6 is methoxymethyl; A7 is C—R7,A8 is N and A9 is C—R9; R7, R9, R10 and R11 are selected independentlyof each other from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆alkoxyand OR12; and wherein R12 represents a monocyclic saturated ring moietyhaving 4-6 ring atoms wherein one of said ring atoms is O and the restis C; or a pharmaceutical acceptable salt thereof.
 2. The methodaccording to claim 1, wherein the compound is selected from: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt of any of these compounds.
 3. Themethod according to claim 1, wherein the compound is: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; or apharmaceutical acceptable salt thereof.
 4. The method according to claim1, wherein the compound is: 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 5. The method according toclaim 1, wherein the compound is: 48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 6. The method according toclaim 1, wherein the compound is: 49:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt thereof.
 7. A method for thetreatment of cognitive impairment associated with schizophrenia, saidmethod comprising administering a therapeutically effective amount of acompound according to formula [I] to a patient in need thereof,

wherein: R1, R2, R3, R4 and R5 are H; R6 is methoxymethyl; A7 is C—R7,A8 is N and A9 is C—R9; R7, R9, R10 and R11 are selected independentlyof each other from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxyand OR12; and wherein R12 represents a monocyclic saturated ring moietyhaving 4-6 ring atoms wherein one of said ring atoms is O and the restis C; or a pharmaceutical acceptable salt thereof.
 8. The methodaccording to claim 7, wherein the compound is selected from: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt of any of these compounds.
 9. Themethod according to claim 7, wherein the compound is: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; or apharmaceutical acceptable salt thereof.
 10. The method according toclaim 7, wherein the compound is: 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 11. The method according toclaim 7, wherein the compound is: 48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 12. The method according toclaim 7, wherein the compound is: 49:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt thereof.
 13. A method for thetreatment of a cognitive disorder, said method comprising administeringa therapeutically effective amount of a compound according to formula[I] to a patient in need thereof,

wherein: R1, R2, R3, R4 and R5 are H; R6 is methoxymethyl; A7 is C—R7,A8 is N and A9 is C—R9; R7, R9, R10 and R11 are selected independentlyof each other from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxyand OR12; and wherein R12 represents a monocyclic saturated ring moietyhaving 4-6 ring atoms wherein one of said ring atoms is O and the restis C; or a pharmaceutical acceptable salt thereof.
 14. The methodaccording to claim 13, wherein the compound is selected from: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt of any of these compounds.
 15. Themethod according to claim 13, wherein the compound is: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; or apharmaceutical acceptable salt thereof.
 16. The method according toclaim 13, wherein the compound is: 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 17. The method according toclaim 13, wherein the compound is: 48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 18. The method according toclaim 13, wherein the compound is: 49:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt thereof.
 19. A method for thetreatment of mild cognitive impairment, said method comprisingadministering a therapeutically effective amount of a compound accordingto formula [I] to a patient in need thereof,

wherein: R1, R2, R3, R4 and R5 are H; R6 is methoxymethyl; A7 is C—R7,A8 is N and A9 is C—R9; R7, R9, R10 and R11 are selected independentlyof each other from H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxyand OR12; and wherein R12 represents a monocyclic saturated ring moietyhaving 4-6 ring atoms wherein one of said ring atoms is O and the restis C; or a pharmaceutical acceptable salt thereof.
 20. The methodaccording to claim 19, wherein the compound is selected from: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;49: (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt of any of these compounds.
 21. Themethod according to claim 19, wherein the compound is: 46:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid[(R)-1-(6-ethoxy-pyridin-3-yl)-2-methoxy-ethyl]-amide; or apharmaceutical acceptable salt thereof.
 22. The method according toclaim 19, wherein the compound is: 47:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3R)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 23. The method according toclaim 19, wherein the compound is: 48:(1S,2S)—N-[(1R)-2-methoxy-1-[6-[(3S)-tetrahydrofuran-3-yl]oxy-3-pyridyl]ethyl]-2-phenyl-cyclopropanecarboxamide;or a pharmaceutical acceptable salt thereof.
 24. The method according toclaim 19, wherein the compound is 49:(1S,2S)-2-Phenyl-cyclopropanecarboxylic acid{(R)-2-methoxy-1-[6-(tetrahydro-pyran-4-yloxy)-pyridin-3-yl]-ethyl}-amide;or a pharmaceutical acceptable salt thereof.
 25. The method of claim 1,wherein the method further comprises the administration of atherapeutically effective amount of a second compound wherein the secondcompound is selected from the group consisting of: acetylcholinesteraseinhibitors; glutamate receptor antagonists; dopamine transportinhibitors; noradrenalin transport inhibitors; D2 antagonists; D2partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABAsignaling enhancers.
 26. The method of claim 7, wherein the methodfurther comprises the administration of a therapeutically effectiveamount of a second compound wherein the second compound is selected fromthe group consisting of: acetylcholinesterase inhibitors; glutamatereceptor antagonists; dopamine transport inhibitors; noradrenalintransport inhibitors; D2 antagonists; D2 partial agonists; PDE10antagonists; 5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists;lithium; sodium channel blockers and GABA signaling enhancers.
 27. Themethod of claim 13, wherein the method further comprises theadministration of a therapeutically effective amount of a secondcompound wherein the second compound is selected from the groupconsisting of: acetylcholinesterase inhibitors; glutamate receptorantagonists; dopamine transport inhibitors; noradrenalin transportinhibitors; D2 antagonists; D2 partial agonists; PDE10 antagonists;5-HT2A antagonists; 5-HT6 antagonists; KCNQ antagonists; lithium; sodiumchannel blockers and GABA signaling enhancers.
 28. The method of claim19, wherein the method further comprises the administration of atherapeutically effective amount of a second compound wherein the secondcompound is selected from the group consisting of: acetylcholinesteraseinhibitors; glutamate receptor antagonists; dopamine transportinhibitors; noradrenalin transport inhibitors; D2 antagonists; D2partial agonists; PDE10 antagonists; 5-HT2A antagonists; 5-HT6antagonists; KCNQ antagonists; lithium; sodium channel blockers and GABAsignaling enhancers.